Publications by authors named "Rachel Pearlman"

27 Publications

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Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Authors:
Jeroen R Huyghe Tabitha A Harrison Stephanie A Bien Heather Hampel Jane C Figueiredo Stephanie L Schmit David V Conti Sai Chen Conghui Qu Yi Lin Richard Barfield John A Baron Amanda J Cross Brenda Diergaarde David Duggan Sophia Harlid Liher Imaz Hyun Min Kang David M Levine Vittorio Perduca Aurora Perez-Cornago Lori C Sakoda Fredrick R Schumacher Martha L Slattery Amanda E Toland Fränzel J B van Duijnhoven Bethany Van Guelpen Antonio Agudo Demetrius Albanes M Henar Alonso Kristin Anderson Coral Arnau-Collell Volker Arndt Barbara L Banbury Michael C Bassik Sonja I Berndt Stéphane Bézieau D Timothy Bishop Juergen Boehm Heiner Boeing Marie-Christine Boutron-Ruault Hermann Brenner Stefanie Brezina Stephan Buch Daniel D Buchanan Andrea Burnett-Hartman Bette J Caan Peter T Campbell Prudence R Carr Antoni Castells Sergi Castellví-Bel Andrew T Chan Jenny Chang-Claude Stephen J Chanock Keith R Curtis Albert de la Chapelle Douglas F Easton Dallas R English Edith J M Feskens Manish Gala Steven J Gallinger W James Gauderman Graham G Giles Phyllis J Goodman William M Grady John S Grove Andrea Gsur Marc J Gunter Robert W Haile Jochen Hampe Michael Hoffmeister John L Hopper Wan-Ling Hsu Wen-Yi Huang Thomas J Hudson Mazda Jenab Mark A Jenkins Amit D Joshi Temitope O Keku Charles Kooperberg Tilman Kühn Sébastien Küry Loic Le Marchand Flavio Lejbkowicz Christopher I Li Li Li Wolfgang Lieb Annika Lindblom Noralane M Lindor Satu Männistö Sanford D Markowitz Roger L Milne Lorena Moreno Neil Murphy Rami Nassir Kenneth Offit Shuji Ogino Salvatore Panico Patrick S Parfrey Rachel Pearlman Paul D P Pharoah Amanda I Phipps Elizabeth A Platz John D Potter Ross L Prentice Lihong Qi Leon Raskin Gad Rennert Hedy S Rennert Elio Riboli Clemens Schafmayer Robert E Schoen Daniela Seminara Mingyang Song Yu-Ru Su Catherine M Tangen Stephen N Thibodeau Duncan C Thomas Antonia Trichopoulou Cornelia M Ulrich Kala Visvanathan Pavel Vodicka Ludmila Vodickova Veronika Vymetalkova Korbinian Weigl Stephanie J Weinstein Emily White Alicja Wolk Michael O Woods Anna H Wu Goncalo R Abecasis Deborah A Nickerson Peter C Scacheri Anshul Kundaje Graham Casey Stephen B Gruber Li Hsu Victor Moreno Richard B Hayes Polly A Newcomb Ulrike Peters

Gut 2021 Feb 25. Epub 2021 Feb 25.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
February 2021

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients.

Gynecol Oncol 2021 Jan 21;160(1):161-168. Epub 2020 Oct 21.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, OH, United States of America.

Objective: Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.

Methods: 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13-12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.

Results: Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).

Conclusions: Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783191PMC
January 2021

A High Percentage of Early-age Onset Colorectal Cancer Is Potentially Preventable.

Gastroenterology 2020 Dec 11. Epub 2020 Dec 11.

Department of Internal Medicine and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.12.009DOI Listing
December 2020

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Gastroenterology 2020 Oct 12. Epub 2020 Oct 12.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Background And Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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http://dx.doi.org/10.1053/j.gastro.2020.08.062DOI Listing
October 2020

Unexpected expression of mismatch repair protein is more commonly seen with pathogenic missense than with other mutations in Lynch syndrome.

Hum Pathol 2020 09 8;103:34-41. Epub 2020 Jul 8.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

It has been observed that some patients with colorectal cancer due to germline or double somatic pathogenic variants in the mismatch repair (MMR) genes may have intact protein expression in their tumors as assessed by immunohistochemistry (IHC). This has been speculated to occur more frequently in Lynch syndrome (LS) cases due to pathogenic missense mutations, leading to expression of a full-length but nonfunctional protein with retained antigenicity. Our goals were to study the frequency of unexpected MMR expression in colorectal cancers among LS cases with missense mutations, LS cases with truncating mutations, as well as cases with double somatic MMR mutations and evaluate if the unexpected MMR expression is more common in certain categories. IHC slides were available for 82 patients with MMR deficiency without methylation, which included 56 LS cases and 26 double somatic MMR mutation cases. Sixteen of 82 MMR-defective cases showed unexpected MMR expression, with 10 cases showing tumor staining weaker than the control and 6 cases (7%) showing intact staining. Unexpected MMR expression was most commonly seen with LS cases with missense mutations (4 of 9, 44%), followed by MMR double somatic mutation cases (7 of 26, 27%), and finally by LS cases with truncating mutations (5 of 47, 11%). Cautious interpretation of MMR IHC is advised when dealing with tumor staining that is weaker than the control regardless of the percentage of tumor staining as these cases may harbor pathogenic MMR gene mutations. Missense mutations may account for some LS cases that may be missed by IHC alone. Strict adherence to proper interpretation of IHC with attention to staining intensity and the status of heterodimer partner protein will prevent many potential misses.
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http://dx.doi.org/10.1016/j.humpath.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664304PMC
September 2020

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Authors:
Alexi N Archambault Yu-Ru Su Jihyoun Jeon Minta Thomas Yi Lin David V Conti Aung Ko Win Lori C Sakoda Iris Lansdorp-Vogelaar Elisabeth F P Peterse Ann G Zauber David Duggan Andreana N Holowatyj Jeroen R Huyghe Hermann Brenner Michelle Cotterchio Stéphane Bézieau Stephanie L Schmit Christopher K Edlund Melissa C Southey Robert J MacInnis Peter T Campbell Jenny Chang-Claude Martha L Slattery Andrew T Chan Amit D Joshi Mingyang Song Yin Cao Michael O Woods Emily White Stephanie J Weinstein Cornelia M Ulrich Michael Hoffmeister Stephanie A Bien Tabitha A Harrison Jochen Hampe Christopher I Li Clemens Schafmayer Kenneth Offit Paul D Pharoah Victor Moreno Annika Lindblom Alicja Wolk Anna H Wu Li Li Marc J Gunter Andrea Gsur Temitope O Keku Rachel Pearlman D Timothy Bishop Sergi Castellví-Bel Leticia Moreira Pavel Vodicka Ellen Kampman Graham G Giles Demetrius Albanes John A Baron Sonja I Berndt Stefanie Brezina Stephan Buch Daniel D Buchanan Antonia Trichopoulou Gianluca Severi María-Dolores Chirlaque Maria-José Sánchez Domenico Palli Tilman Kühn Neil Murphy Amanda J Cross Andrea N Burnett-Hartman Stephen J Chanock Albert de la Chapelle Douglas F Easton Faye Elliott Dallas R English Edith J M Feskens Liesel M FitzGerald Phyllis J Goodman John L Hopper Thomas J Hudson David J Hunter Eric J Jacobs Corinne E Joshu Sébastien Küry Sanford D Markowitz Roger L Milne Elizabeth A Platz Gad Rennert Hedy S Rennert Fredrick R Schumacher Robert S Sandler Daniela Seminara Catherine M Tangen Stephen N Thibodeau Amanda E Toland Franzel J B van Duijnhoven Kala Visvanathan Ludmila Vodickova John D Potter Satu Männistö Korbinian Weigl Jane Figueiredo Vicente Martín Susanna C Larsson Patrick S Parfrey Wen-Yi Huang Heinz-Josef Lenz Jose E Castelao Manuela Gago-Dominguez Victor Muñoz-Garzón Christoph Mancao Christopher A Haiman Lynne R Wilkens Erin Siegel Elizabeth Barry Ban Younghusband Bethany Van Guelpen Sophia Harlid Anne Zeleniuch-Jacquotte Peter S Liang Mengmeng Du Graham Casey Noralane M Lindor Loic Le Marchand Steven J Gallinger Mark A Jenkins Polly A Newcomb Stephen B Gruber Robert E Schoen Heather Hampel Douglas A Corley Li Hsu Ulrike Peters Richard B Hayes

Gastroenterology 2020 04 19;158(5):1274-1286.e12. Epub 2019 Dec 19.

Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York. Electronic address:

Background & Aims: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

Methods: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.

Results: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.

Conclusions: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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http://dx.doi.org/10.1053/j.gastro.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103489PMC
April 2020

MSH6 immunohistochemical heterogeneity in colorectal cancer: comparative sequencing from different tumor areas.

Hum Pathol 2020 02 27;96:104-111. Epub 2019 Nov 27.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210. Electronic address:

Mismatch repair protein (MMR) immunohistochemistry is an important tool in screening for Lynch syndrome in colorectal cancer patients. Unusual staining patterns such as heterogeneous MSH6 staining have been reported in colorectal and endometrial cancers. We aim to better understand MSH6 staining heterogeneity in colorectal cancer by comparative sequencing of different tumor areas for MMR and DNA polymerase mutations. Whole-section slides of 1754 colorectal cancers were reviewed for heterogeneous MSH6 staining, defined as discrete tumor areas with abrupt loss of staining juxtaposed to tumor areas with retained staining. Nine cases (0.05%) demonstrated heterogeneous MSH6 staining; none received neoadjuvant therapy prior to the specimen collection. The area of tumor with loss of MSH6 expression ranged from 5% to 60% (average 22%). Four cases had enough tissue remaining in both retained and lost MSH6 areas to perform tumor sequencing on both areas. All 9 cases were negative for MSH6 germline mutation; MSH6 heterogeneous staining was seen in tumors with MLH1 or PMS2 abnormalities (6 cases of MLH1 methylation, 2 PMS2 germline mutation, 1 MLH1 germline mutation). In addition, case 1 also had a somatic POLD1 exonuclease domain mutation (p.Y405C) in the MSH6 loss area but not in the intact area. We recommend reporting MSH6 heterogeneous pattern as MSH6 staining is present with a comment stating that the heterogeneous pattern typically does not indicate germline mutation in MSH6 but is commonly associated with abnormality in another MMR gene such as MLH1 or PMS2, or even other DNA repair genes such as DNA polymerase.
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http://dx.doi.org/10.1016/j.humpath.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191319PMC
February 2020

Hereditary or Not? Understanding Serrated Polyposis Syndrome.

Curr Treat Options Gastroenterol 2019 Dec;17(4):692-701

Division of Human Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Purpose Of Review: To present the current understanding of the diagnosis, management, and potential genetic causes of serrated polyposis syndrome.

Recent Findings: The clinical criteria for serrated polyposis syndrome was recently updated and now includes individuals with five or more serrated polyps proximal to the rectum that are 5 mm in size or greater and at least two that are 10 mm in size of greater as well as individuals with 20 or more serrated polyps throughout the colon with at least five proximal to the rectum. There is a significant risk for colon cancer in first-degree relatives of individuals with serrated polyposis syndrome. However, less than 3% of serrated polyposis syndrome cases are explained by identifiable germline mutations, with mutations in RNF43 being the only currently validated genetic cause. Serrated polyposis syndrome is rarely explained by identifiable germline mutations, but there remains an increased risk for colorectal cancer in first-degree relatives. Referral for genetic counseling and testing is recommended for individuals with serrated polyposis syndrome and a personal history of coexisting adenomatous polyposis or with a concerning family history and can be considered for all individuals with serrated polyposis syndrome. Close endoscopic surveillance of those with serrated polyposis syndrome and their first-degree relatives is recommended. Continued efforts at identifying hereditary causes of serrated polyposis are needed.
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http://dx.doi.org/10.1007/s11938-019-00256-zDOI Listing
December 2019

Comparative Effectiveness of Two Interventions to Increase Colorectal Cancer Screening for Those at Increased Risk Based on Family History: Results of a Randomized Trial.

Cancer Epidemiol Biomarkers Prev 2020 01 30;29(1):3-9. Epub 2019 Oct 30.

Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Background: First-degree relatives (FDR) of patients with colorectal cancer are at risk for colorectal cancer, but may not be up to date with colorectal cancer screening. We sought to determine whether a one-time recommendation about needing colorectal cancer screening using patient navigation (PN) was better than just receiving the recommendation only.

Methods: Participants were FDRs of patients with Lynch syndrome-negative colorectal cancer from participating Ohio hospitals. FDRs from 259 families were randomized to a website intervention (528 individuals), which included a survey and personal colorectal cancer screening recommendation, while those from 254 families were randomized to the website plus telephonic PN intervention (515 individuals). Primary outcome was adherence to the personal screening recommendation (to get screened or not to get screened) received from the website. Secondary outcomes examined who benefited from adding PN.

Results: At the end of the 14-month follow-up, 78.6% of participants were adherent to their recommendation for colorectal cancer screening with adherence similar between arms ( = 0.14). Among those who received a recommendation to have a colonoscopy immediately, the website plus PN intervention significantly increased the odds of receiving screening, compared with the website intervention (OR: 2.98; 95% confidence interval, 1.68-5.28).

Conclusions: Addition of PN to a website intervention did not improve adherence to a colorectal cancer screening recommendation overall; however, the addition of PN was more effective in increasing adherence among FDRs who needed screening immediately.

Impact: These findings provide important information as to when the additional costs of PN are needed to assure colorectal cancer screening among those at high risk for colorectal cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954294PMC
January 2020

Methylated plasma test for colorectal cancer detection may be applicable to Lynch syndrome.

BMJ Open Gastroenterol 2019 28;6(1):e000299. Epub 2019 May 28.

Hereditary Cancer Center, Creighton University, Omaha, Nebraska, USA.

Objective: The plasma-based methylated (mSEPT9) is a colorectal cancer (CRC) screening test for adults aged 50-75 years who are at average risk for CRC and have refused colonoscopy or faecal-based screening tests. The applicability of mSEPT9 for high-risk persons with Lynch syndrome (LS), the most common hereditary CRC condition, has not been assessed. This study sought preliminary evidence for the utility of mSEPT9 for CRC detection in LS.

Design: Firstly, SEPT9 methylation was measured in LS-associated CRC, advanced adenoma, and subject-matched normal colorectal mucosa tissues by pyrosequencing. Secondly, to detect mSEPT9 as circulating tumor DNA, the plasma-based mSEPT9 test was retrospectively evaluated in LS subjects using the Epi proColon 2.0 CE assay adapted for 1mL plasma using the "1/1 algorithm". LS case groups included 20 peri-surgical cases with acolonoscopy-based diagnosis of CRC (stages I-IV), 13 post-surgical metastatic CRC, and 17 pre-diagnosis cases. The control group comprised 31 cancer-free LS subjects.

Results: Differential hypermethylation was found in 97.3% (36/37) of primary CRC and 90.0% (18/20) of advanced adenomas, showing LS-associated neoplasia frequently produce the mSEPT9 biomarker. Sensitivity of plasma mSEPT9 to detect CRC was 70.0% (95% CI, 48%-88%)in cases with a colonoscopy-based CRC diagnosis and 92.3% (95% CI, 64%-100%) inpost-surgical metastatic cases. In pre-diagnosis cases, plasma mSEPT9 was detected within two months prior to colonoscopy-based CRC diagnosis in 3/5 cases. Specificity in controls was 100% (95% CI 89%-100%).

Conclusion: These preliminary findings suggest mSEPT9 may demonstrate similar diagnostic performance characteristics in LS as in the average-risk population, warranting a well-powered prospective case-control study.
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http://dx.doi.org/10.1136/bmjgast-2019-000299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577308PMC
May 2019

"Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome"-reply.

Hum Pathol 2019 07 7;89:116-117. Epub 2019 May 7.

Department of Internal Medicine, Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH.; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH.. Electronic address:

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http://dx.doi.org/10.1016/j.humpath.2019.04.017DOI Listing
July 2019

Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome.

J Med Genet 2019 07 15;56(7):462-470. Epub 2019 Mar 15.

Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background: Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts.

Methods: We included patients with CRC from Ohio 2013-2016 and Iceland 2000-2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared.

Results: Of the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10) and have multiple LS-associated tumours (OR=6.67, p=3.31×10). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts.

Conclusions: Individuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS.
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http://dx.doi.org/10.1136/jmedgenet-2018-105698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748629PMC
July 2019

Prevalence of Germline Mutations in Polyposis and Colorectal Cancer-Associated Genes in Patients With Multiple Colorectal Polyps.

Clin Gastroenterol Hepatol 2019 09 14;17(10):2008-2015.e3. Epub 2018 Dec 14.

Ambry Genetics, Aliso Viejo, California.

Background And Aims: Guidelines recommend genetic testing of patients with 10 or more cumulative adenomatous polyps. However, little is known about the utility of these tests-especially for older patients. We aimed to determine the prevalence of pathogenic mutations in patients with multiple colorectal polyps, stratified by age.

Methods: We performed a cross-sectional study of patients with 10 or more colorectal polyps who underwent multigene panel testing (MGPT) from March 2012 through December 2016 (n = 3789). Demographic, clinical and family history data were obtained from test requisition forms and accompanying clinic notes, pedigrees, and pathology reports. Subjects were stratified based on reported polyp histology. Primary outcomes of interest were gene mutations associated with adenomatous polyposis, hamartomatous polyposis, and non-polyposis colorectal cancer syndromes.

Results: Based on MGPT, the prevalence of mutations in adenomatous polyposis genes decreased with increasing age in all polyp count groups in the adenoma cohort (P < .001 for 10-19, 20-99, and 100 or more polyps). The prevalence of mutations in all genes of interest also decreased with increasing age but remained above 5% in all age and polyp cohorts. Increased age at testing was associated with a significantly lower risk of a mutation in any gene of interest with multivariate analysis. In the hamartoma cohort, the prevalence of mutations in hamartomatous polyposis genes was high regardless of polyp count (40% with 10-19 polyps, 72.1% with 20-99 polyps, and 50% with 100 or more polyps).

Conclusion: Our findings support continued genetic testing of patients with 10 or more polyps including adenomas and/or hamartomas. MGPT that includes analysis of polyposis and non-polyposis colorectal cancer genes should be considered for these patients given the high proportion with mutations (above 5%) in all age groups.
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http://dx.doi.org/10.1016/j.cgh.2018.12.008DOI Listing
September 2019

Discovery of common and rare genetic risk variants for colorectal cancer.

Authors:
Jeroen R Huyghe Stephanie A Bien Tabitha A Harrison Hyun Min Kang Sai Chen Stephanie L Schmit David V Conti Conghui Qu Jihyoun Jeon Christopher K Edlund Peyton Greenside Michael Wainberg Fredrick R Schumacher Joshua D Smith David M Levine Sarah C Nelson Nasa A Sinnott-Armstrong Demetrius Albanes M Henar Alonso Kristin Anderson Coral Arnau-Collell Volker Arndt Christina Bamia Barbara L Banbury John A Baron Sonja I Berndt Stéphane Bézieau D Timothy Bishop Juergen Boehm Heiner Boeing Hermann Brenner Stefanie Brezina Stephan Buch Daniel D Buchanan Andrea Burnett-Hartman Katja Butterbach Bette J Caan Peter T Campbell Christopher S Carlson Sergi Castellví-Bel Andrew T Chan Jenny Chang-Claude Stephen J Chanock Maria-Dolores Chirlaque Sang Hee Cho Charles M Connolly Amanda J Cross Katarina Cuk Keith R Curtis Albert de la Chapelle Kimberly F Doheny David Duggan Douglas F Easton Sjoerd G Elias Faye Elliott Dallas R English Edith J M Feskens Jane C Figueiredo Rocky Fischer Liesel M FitzGerald David Forman Manish Gala Steven Gallinger W James Gauderman Graham G Giles Elizabeth Gillanders Jian Gong Phyllis J Goodman William M Grady John S Grove Andrea Gsur Marc J Gunter Robert W Haile Jochen Hampe Heather Hampel Sophia Harlid Richard B Hayes Philipp Hofer Michael Hoffmeister John L Hopper Wan-Ling Hsu Wen-Yi Huang Thomas J Hudson David J Hunter Gemma Ibañez-Sanz Gregory E Idos Roxann Ingersoll Rebecca D Jackson Eric J Jacobs Mark A Jenkins Amit D Joshi Corinne E Joshu Temitope O Keku Timothy J Key Hyeong Rok Kim Emiko Kobayashi Laurence N Kolonel Charles Kooperberg Tilman Kühn Sébastien Küry Sun-Seog Kweon Susanna C Larsson Cecelia A Laurie Loic Le Marchand Suzanne M Leal Soo Chin Lee Flavio Lejbkowicz Mathieu Lemire Christopher I Li Li Li Wolfgang Lieb Yi Lin Annika Lindblom Noralane M Lindor Hua Ling Tin L Louie Satu Männistö Sanford D Markowitz Vicente Martín Giovanna Masala Caroline E McNeil Marilena Melas Roger L Milne Lorena Moreno Neil Murphy Robin Myte Alessio Naccarati Polly A Newcomb Kenneth Offit Shuji Ogino N Charlotte Onland-Moret Barbara Pardini Patrick S Parfrey Rachel Pearlman Vittorio Perduca Paul D P Pharoah Mila Pinchev Elizabeth A Platz Ross L Prentice Elizabeth Pugh Leon Raskin Gad Rennert Hedy S Rennert Elio Riboli Miguel Rodríguez-Barranco Jane Romm Lori C Sakoda Clemens Schafmayer Robert E Schoen Daniela Seminara Mitul Shah Tameka Shelford Min-Ho Shin Katerina Shulman Sabina Sieri Martha L Slattery Melissa C Southey Zsofia K Stadler Christa Stegmaier Yu-Ru Su Catherine M Tangen Stephen N Thibodeau Duncan C Thomas Sushma S Thomas Amanda E Toland Antonia Trichopoulou Cornelia M Ulrich David J Van Den Berg Franzel J B van Duijnhoven Bethany Van Guelpen Henk van Kranen Joseph Vijai Kala Visvanathan Pavel Vodicka Ludmila Vodickova Veronika Vymetalkova Korbinian Weigl Stephanie J Weinstein Emily White Aung Ko Win C Roland Wolf Alicja Wolk Michael O Woods Anna H Wu Syed H Zaidi Brent W Zanke Qing Zhang Wei Zheng Peter C Scacheri John D Potter Michael C Bassik Anshul Kundaje Graham Casey Victor Moreno Goncalo R Abecasis Deborah A Nickerson Stephen B Gruber Li Hsu Ulrike Peters

Nat Genet 2019 01 3;51(1):76-87. Epub 2018 Dec 3.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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http://dx.doi.org/10.1038/s41588-018-0286-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358437PMC
January 2019

Cancer Risks for PMS2-Associated Lynch Syndrome.

J Clin Oncol 2018 10 30;36(29):2961-2968. Epub 2018 Aug 30.

Sanne W. ten Broeke, Heleen M. van der Klift, Carli M.J. Tops, Manon Suerink, Frederik J. Hes, Hans F.A. Vasen, Juul T. Wijnen, and Maartje Nielsen, Leiden University Medical Center, Leiden; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Tom G.W. Letteboer, University Medical Center, Utrecht; Theo A.M. van Os and Egbert J.W. Redeker, Academic Medical Center, Amsterdam; Maran J.W. Olderode-Berends and Yvonne J. Vos, University of Groningen; University Medical Center Groningen, Groningen; Anja Wagner, Erasmus Medical Center, Rotterdam, the Netherlands; Stefan Aretz, University of Bonn; University Hospital Bonn, Bonn; Christoph Engel, Leipzig University; Medizinisch Genetisches Zentrum Bayerstr, Leipzig; Magnus von Knebel Doeberitz, University of Heidelberg; German Cancer Research Center, Heidelberg; Pål Møller, University of Witten-Herdecke, Wuppertal; Nils Rahner, Heinrich-Heine-University, Düsseldorf; Hans K. Schackert, Technische Universität Dresden, Dresden; Verena Steinke-Lange, Medizinische Klinik und Poliklinik IV Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Pål Møller, The Norwegian Radium Hospital; Oslo University Hospital, Oslo, Norway; Inge Bernstein, Hvidovre Hospital, Hvidovre, and Aalborg University Hospital, Aalborg, Denmark; Daniel D. Buchanan, Mark Clendenning, John L. Hopper, Mark A. Jenkins, Christophe Rosty, Ingrid Winship, and Aung Ko Win, The University of Melbourne; Daniel D. Buchanan, Ingrid Winship, and Aung Ko Win, Royal Melbourne Hospital, Parkville, Melbourne, Victoria; Rodney Scott, University of Newcastle, Newcastle, New South Wales, Australia; Albert de la Chapelle, Heather L. Hampel, Rachel Pearlman, and Leigha Senter, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Gabriel Capella and Marta Pineda, Institut d'Investigació Biomédica de Bellvitge, Barcelona, Spain; Steven Gallinger, Mount Sinai Hospital, Toronto, Ontario, Canada; Jane C. Figueiredo and Robert Haile, Cedars-Sinai Medical Center, Los Angeles, CA; Loic Le Marchand, University of Hawaii Cancer Center, Honolulu, HI; Annika Lindblom, Karolinska Institutet; Karolinska University Hospital, Stockholm, Sweden; Noralane M. Lindor, Mayo Clinic Arizona, Scottsdale, AZ; Polly A. Newcomb, Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA; and Stephen Thibodeau, Mayo Clinic, Rochester, MN.

Purpose: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.

Methods: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance.

Results: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.

Conclusion: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
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http://dx.doi.org/10.1200/JCO.2018.78.4777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349460PMC
October 2018

Modified capture-recapture estimates of the number of families with Lynch syndrome in Central Ohio.

Fam Cancer 2019 01;18(1):67-73

Department of Laboratory Medicine, University of Washington, 1959 NE Pacific Street, NW120, Box 357110, Seattle, WA, 98195-7110, USA.

Past methods for estimating the population frequency of familial cancer syndromes have used cases and controls ignoring the familial nature of genetic disease. In this study we modified the capture-recapture method from ecology to estimate the number of families in central Ohio with Lynch syndrome (LS). We screened 1566 colorectal cancer cases and 545 endometrial cancer cases in central Ohio from 1999 to 2005 and identified 58 with LS. We screened an additional 3346 colorectal and 342 endometrial cancer cases from 2013 to 2016 and identified 149 with LS. We found 12 LS mutations shared between families observed in the first and second studies. We identified three individuals between studies who were closely related and eight who were more distantly related. We used identified family relationships and genetic test results to estimate family size and structure. Applying a modified capture-recapture method we estimate 1693 3-generation families in the area who have 288 unique LS causing mutations. Comprehensive colorectal and endometrial cancer screening will take about 20 years to identify 50% of families with LS. This is the first time that the capture-recapture method has been applied to estimate the burden of families with a specific heritable disease. Family structure reveals the potential extent of prevention and the time necessary to identify a proportion of families with LS.
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http://dx.doi.org/10.1007/s10689-018-0096-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324998PMC
January 2019

Two-stain immunohistochemical screening for Lynch syndrome in colorectal cancer may fail to detect mismatch repair deficiency.

Mod Pathol 2018 12 2;31(12):1891-1900. Epub 2018 Jul 2.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Universal screening for Lynch syndrome in colorectal cancer is recommended, and immunohistochemistry for the mismatch repair proteins is commonly used. To reduce cost, some screen using only MSH6 and PMS2, with reflex to the partner stain if either are absent (two-stain method). An expression pattern revealing absent MSH2 and intact MSH6 is not expected, but could result in failed Lynch syndrome detection. We analyzed tumors with absent MSH2 but any degree of MSH6 expression to determine if the two-stain method could miss MSH2 mutations. One-thousand seven-hundred thirty colorectal cancer patients from the Ohio Colorectal Cancer Prevention Initiative underwent tumor screening using microsatellite instability and immunohistochemistry. The two-stain method was used for 1235 cases; staining for all four proteins was completed for 495 cases. The proportion of positive cells and staining intensity were reviewed for MSH6, as well as MSH2 when available. Patients with mismatch repair deficiency underwent next-generation sequencing of germline DNA for mismatch repair genes. If negative, tumor next-generation sequencing was performed to assess for somatic mutations. Overall, thirty-three (1.9%, 33/1730) MSH2-absent cases were identified. Of those, fourteen had no MSH6 expression but eight (0.5%, 8/1730) had ambiguous and eleven (0.6%, 11/1730) had convincing MSH6 expression that could have been interpreted as intact. Germline next-generation sequencing identified MSH2 mutations in 11/14 cases with absence of both stains, 7/8 cases with ambiguous MSH6 expression, and 9/11 cases with convincing MSH6 expression. All remaining cases, except one, had double somatic mutations. The two-stain method fails to detect some patients with Lynch syndrome: (1) significant staining weaker than the control may be incorrectly interpreted as intact MSH6, or (2) Weak or focal/patchy MSH6 can be retained with the absence of MSH2. Accordingly, we recommend the four-stain method be used for optimal Lynch syndrome screening detection.
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http://dx.doi.org/10.1038/s41379-018-0058-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800091PMC
December 2018

Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.

Am J Hum Genet 2018 07 7;103(1):19-29. Epub 2018 Jun 7.

Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.

Present guidelines for classification of constitutional variants do not incorporate inferences from mutations seen in tumors, even when these are associated with a specific molecular phenotype. When somatic mutations and constitutional mutations lead to the same molecular phenotype, as for the mismatch repair genes, information from somatic mutations may enable interpretation of previously unclassified variants. To test this idea, we first estimated likelihoods that somatic variants in MLH1, MSH2, MSH6, and PMS2 drive microsatellite instability and characteristic IHC staining patterns by calculating likelihoods of high versus low normalized variant read fractions of 153 mutations known to be pathogenic versus those of 760 intronic passenger mutations from 174 paired tumor-normal samples. Mutations that explained the tumor mismatch repair phenotype had likelihood ratio for high variant read fraction of 1.56 (95% CI 1.42-1.71) at sites with no loss of heterozygosity and of 26.5 (95% CI 13.2-53.0) at sites with loss of heterozygosity. Next, we applied these ratios to 165 missense, synonymous, and splice variants observed in tumors, combining in a Bayesian analysis the likelihood ratio corresponding with the adjusted variant read fraction with pretest probabilities derived from published analyses and public databases. We suggest classifications for 86 of 165 variants: 7 benign, 31 likely benign, 22 likely pathogenic, and 26 pathogenic. These results illustrate that for mismatch repair genes, characterization of tumor mutations permits tumor mutation data to inform constitutional variant classification. We suggest modifications to incorporate molecular phenotype in future variant classification guidelines.
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http://dx.doi.org/10.1016/j.ajhg.2018.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035155PMC
July 2018

Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome.

Hum Pathol 2018 08 1;78:125-130. Epub 2018 May 1.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address:

Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.
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http://dx.doi.org/10.1016/j.humpath.2018.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296362PMC
August 2018

Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer.

JAMA Oncol 2018 06;4(6):806-813

Department of Laboratory Medicine, University of Washington, Seattle.

Importance: Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol.

Objective: To determine whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for LS.

Design, Setting, And Participants: Tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016 (the prospective cohort) and 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 (the validation cohort) underwent blinded TS.

Main Outcomes And Measures: Sensitivity of TS compared with microsatellite instability (MSI) testing and immunohistochemical (IHC) staining for the detection of LS.

Results: In the 465 patients, mean age at diagnosis was 59.9 years (range, 20-96 years), and 241 (51.8%) were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF p.V600E testing missed 5 and 6 cases of LS, respectively. Tumor sequencing alone had better sensitivity (100%; 95% CI, 93.8%-100%) than IHC plus BRAF (89.7%; 95% CI, 78.8%-96.1%; P = .04) and MSI plus BRAF (91.4%; 95% CI, 81.0%-97.1%; P = .07). Tumor sequencing had equal specificity (95.3%; 95% CI, 92.6%-97.2%) to IHC plus BRAF (94.6%; 95% CI, 91.9%-96.6%; P > .99) and MSI plus BRAF (94.8%; 95% CI, 92.2%-96.8%; P = .88). Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC, avoiding another test. Finally, TS identified 8 patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could also be useful for treatment selection.

Conclusions And Relevance: Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.
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http://dx.doi.org/10.1001/jamaoncol.2018.0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885168PMC
June 2018

Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival.

Gynecol Oncol 2017 09 11;146(3):588-595. Epub 2017 Jul 11.

Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, United States.

Objectives: To determine the relationship between mismatch repair (MMR) classification and clinicopathologic features including tumor volume, and explore outcomes by MMR class in a contemporary cohort.

Methods: Single institution cohort evaluating MMR classification for endometrial cancers (EC). MMR immunohistochemistry (IHC)±microsatellite instability (MSI) testing and reflex MLH1 methylation testing was performed. Tumors with MMR abnormalities by IHC or MSI and MLH1 methylation were classified as epigenetic MMR deficiency while those without MLH1 methylation were classified as probable MMR mutations. Clinicopathologic characteristics were analyzed.

Results: 466 endometrial cancers were classified; 75% as MMR proficient, 20% epigenetic MMR defects, and 5% as probable MMR mutations. Epigenetic MMR defects were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and older age. MMR class was significantly associated with tumor volume, an association not previously reported. The epigenetic MMR defect tumors median volume was 10,220mm compared to 3321mm and 2,846mm, for MMR proficient and probable MMR mutations respectively (P<0.0001). Higher tumor volume was associated with lymph node involvement. Endometrioid EC cases with epigenetic MMR defects had significantly reduced recurrence-free survival (RFS). Among advanced stage (III/IV) endometrioid EC the epigenetic MMR defect group was more likely to recur compared to the MMR proficient group (47.7% vs 3.4%) despite receiving similar adjuvant therapy. In contrast, there was no difference in the number of early stage recurrences for the different MMR classes.

Conclusions: MMR testing that includes MLH1 methylation analysis defines a subset of tumors that have worse prognostic features and reduced RFS.
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http://dx.doi.org/10.1016/j.ygyno.2017.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601318PMC
September 2017

Mutation Frequencies in Patients With Early-Onset Colorectal Cancer-Reply.

JAMA Oncol 2017 11;3(11):1587

Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus.

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http://dx.doi.org/10.1001/jamaoncol.2017.1744DOI Listing
November 2017

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

JAMA Oncol 2017 Apr;3(4):464-471

The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.

Importance: Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined.

Objective: To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC.

Design, Setting, And Participants: Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing.

Main Outcomes And Measures: Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status.

Results: In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation.

Conclusions And Relevance: Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.
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http://dx.doi.org/10.1001/jamaoncol.2016.5194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564179PMC
April 2017

Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes.

Gastroenterology 2016 09 11;151(3):440-447.e1. Epub 2016 Jun 11.

Department of Laboratory Medicine, University of Washington, Seattle, Washington. Electronic address:

Background & Aims: Some colorectal and endometrial tumors with microsatellite instability not attributable to MLH1 hypermethylation or germline mutations contain 2 or more somatic mutations in genes encoding mismatch repair (MMR) proteins. We sought to define the molecular phenotype of this newly recognized tumor subtype.

Methods: From 2 prospective studies of the efficacy of screening for Lynch syndrome, we identified patients with colorectal and endometrial tumors who had 2 or more somatic (but not germline) mutations in genes encoding MMR proteins (double somatic). We determined the frequencies of tumor mutations in PIK3CA, BRAF, KRAS, NRAS, and PTEN by targeted next-generation sequencing and used logistic-regression models to compare them with those from patients with Lynch syndrome, MLH1-hypermethylated, or microsatellite-stable tumors. We validated our findings using independent data sets from The Cancer Genome Atlas.

Results: Among colorectal cancer cases, we found that 14 of 21 (67%) patients with double somatic tumors also had PIK3CA mutations, compared with 4 of 18 (22%) tumors from patients with Lynch syndrome, 2 of 10 (20%) tumors with MLH1 hypermethylation, and 12 of 78 (15%) tumors with microsatellite stability (P < .0001 for patients with double somatic tumors vs other subgroups). Mutations in PIK3CA were detected in all 13 patients with double somatic endometrial cancers (P = .04 compared with other subgroups). We did not detect BRAF mutations in patients with double somatic colorectal tumors or Lynch syndrome. We found highly similar results in a validation cohort from The Cancer Genome Atlas (113 patients with colorectal tumors, 178 endometrial tumors); 100% of double somatic cases had a somatic mutation in PIK3CA (P < .0001 compared with other subgroups).

Conclusions: Most patients with colorectal or endometrial tumors with 2 or more somatic (but not germline) mutations in MMR proteins also have mutations in PIK3CA; mutations in PIK3CA are detected at substantially higher frequencies in these double somatic tumors than in other microsatellite-instability subgroups. PIK3CA mutation status might be used to identify a specific group of colorectal tumors, and to select treatment or determine prognosis.
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http://dx.doi.org/10.1053/j.gastro.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016834PMC
September 2016

Mismatch repair deficiency concordance between primary colorectal cancer and corresponding metastasis.

Fam Cancer 2016 Apr;15(2):253-60

Department of Pathology, Ohio State University Medical Center, Columbus, OH, USA.

Universal screening for mismatch repair deficiency (dMMR) in cancer is increasingly being implemented to detect Lynch syndrome and aid in treatment decisions. The mismatch repair (MMR) immunohistochemistry (IHC) concordance rate between primary colorectal cancer (CRC) and metastasis is unknown. At times, only metastatic tumor is available for screening (lymph node, liver, lung etc.) rather than the primary tumor. Therefore, it is important to confirm that tissue from metastases can be used for screening for dMMR. We tested dMMR primary and metastatic tumor to assess concordance between the two. We identified dMMR CRC resected at Ohio State University from 1999 to 2013 and stained a corresponding metastasis for all four MMR proteins (MLH1, MSH2, MSH6, PMS2) with IHC. A total of 50 primary CRC with dMMR and available regional lymph nodes (LN; 26 cases) or other metastatic tissue (24 cases) were identified. Thirteen cases were explained by MLH1 hypermethylation and 10 cases had Lynch syndrome. Two cases had somatic MMR mutations and the etiology for dMMR was unknown in 25 cases. All cases showed concordance in IHC staining between the primary tumor and corresponding metastatic tissue. In 36 cases, metastatic LN/other site was resected at the same time as the primary tumor. In 14 cases, time lapsed [median 16.5 months; quartile (Q)1 8.0; Q3 25; range 3-69] from the primary resection until metastatic resection. Metastatic tissue can be used to screen for Lynch syndrome and dMMR.
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http://dx.doi.org/10.1007/s10689-015-9856-2DOI Listing
April 2016

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

Genet Med 2015 Jan 13;17(1):70-87. Epub 2014 Nov 13.

Clinical and Translational Hereditary Cancer Program, Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.

Disclaimer: The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the ACMG and NSGC joint practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are current only as of their publication date, and are subject to change without notice as advances emerge. In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments, and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health-care provider's best medical judgment based on the clinical circumstances of a particular patient or patient population. Practice guidelines are published by the ACMG or the NSGC for educational and informational purposes only, and neither the ACMG nor the NSGC "approve" or "endorse" any specific methods, practices, or sources of information.Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peer-reviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their first-degree relatives meet any of these referral criteria.
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http://dx.doi.org/10.1038/gim.2014.147DOI Listing
January 2015

Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.

Gastroenterology 2014 Dec 3;147(6):1308-1316.e1. Epub 2014 Sep 3.

Department of Laboratory Medicine, University of Washington, Seattle, Washington.

Background & Aims: Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing.

Methods: We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation frequencies were established.

Results: Twenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase.

Conclusions: Some patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines.
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http://dx.doi.org/10.1053/j.gastro.2014.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294551PMC
December 2014