Publications by authors named "Erin Salo-Mullen"

34 Publications

Insertion of an SVA Element in MSH2 as a Novel Cause of Lynch Syndrome.

Genes Chromosomes Cancer 2021 Apr 6. Epub 2021 Apr 6.

Departments of Pathology, New York, NY, US.

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome (LS). In this study, we identified and characterized a novel SINE-VNTR-Alu (SVA) insertion in exon 12 of MSH2 in an individual with early-onset colorectal cancer and a very strong LS family history. RT-PCR analysis indicated a larger aberrant MSH2 transcript in one of the family members. MSK-IMPACT next-generation sequencing and long-range PCR analyses revealed an insertion in MSH2 exon 12 at the c.1972 position in an antisense orientation. The insertion was further characterized as an SVA element approximately 3 kb in length, belonging to the SVA_F1 family of retrotransposons. This variant also segregated with LS related cancers in four affected family members in this family. Based on this evidence, this MSH2 SVA insertion is considered pathogenic. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/gcc.22950DOI Listing
April 2021

Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes.

J Natl Cancer Inst 2021 Mar 23. Epub 2021 Mar 23.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Recent evidence suggests a rising incidence of cancer in younger individuals. Herein, we report the epidemiologic, pathologic, and molecular characteristics of a patient cohort with early-onset pancreas cancer (EOPC).

Methods: Institutional databases were queried for demographics, treatment history, genomic results and outcomes. Overall survival (OS) from date of diagnosis was estimated using Kaplan-Meier method.

Results: Four hundred and fifty patients with EOPC were identified at Memorial Sloan Kettering between 2008 and 2018. Median OS was 16.3 months (95% confidence interval [CI] = 14.6 to 17.7 months) in the entire cohort and 11.3 months (95% CI = 10.2 to 12.2 months) for patients with stage IV disease at diagnosis. One hundred and thirty-two (29.3% of the cohort) underwent somatic testing; 21 of 132 (15.9%) had RAS wild-type cancers with identification of several actionable alterations, including ETV6-NTRK3, TPR-NTRK1, SCLA5-NRG1 and ATP1B1-NRG1 fusions, IDH1 R132C mutation, and mismatch repair deficiency. One hundred and thirty-eight (30.7% of the cohort) underwent germline testing; 44 of 138 (31.9%) had a pathogenic germline variant (PGV) and 27.5% harbored alterations in cancer susceptibility genes. Of patients seen between 2015 and 2018, 30 of 193 (15.5%) had a pathogenic germline variant. Among 138 who underwent germline testing, those with a PGV had a reduced all-cause mortality compared to patients without a PGV controlling for stage and year of diagnosis (hazard ratio = 0.42, 95%CI = 0.26 to 0.69).

Conclusions: PGVs are present in a substantial minority of patients with EOPC. Actionable somatic alterations were identified frequently in EOPC, enriched in the RAS wild-type subgroup. These observations underpin the recent guidelines for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1093/jnci/djab038DOI Listing
March 2021

Resolving pathogenicity classification for the CDH1 c.[715G>A] (p.Gly239Arg) Variant.

Eur J Hum Genet 2021 Feb 22. Epub 2021 Feb 22.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Hereditary Diffuse Gastric Cancer (HDGC) syndrome is associated with CDH1 germline likely pathogenic/pathogenic variants. Carriers of CDH1 germline likely pathogenic/pathogenic variants are predisposed to diffuse gastric cancer and lobular breast cancer. This study aims to classify the CDH1 c.[715G>A] missense variant identified in a diffuse gastric cancer prone family by performing splicing studies. RT-PCR and subsequent cloning experiments were performed to investigate whether this variant completely disrupts normal splicing. This variant preferentially abolishes normal splicing through activation of a cryptic 3' acceptor splice site within exon 6 of CDH1, presumably leading to a premature protein truncation within first extracellular domain repeat of E-cadherin protein. Our results contributed to evidence necessary to resolve pathogenicity classification of this variant, indicating that this variant is to be classified as pathogenic.
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http://dx.doi.org/10.1038/s41431-021-00825-wDOI Listing
February 2021

Insertion of an Alu-like element in MLH1 intron 7 as a novel cause of Lynch syndrome.

Mol Genet Genomic Med 2020 12 15;8(12):e1523. Epub 2020 Oct 15.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Lynch Syndrome (LS) is caused by germline mutations in the DNA mismatch repair (MMR) genes with mutations in MLH1 accounting for ~40% of LS-related alterations.

Methods: MSK-IMPACT analysis was performed on peripheral blood from a patient with early- onset colorectal cancer. Subsequently PCR and sequencing was performed to characterize the insertion. Immunohistochemistry for MMR genes and MLH1 promoter methylation were analyzed on patient's tumor.

Results: MSK-IMPACT germline testing revealed an insertion into c.588+8_588+9 of MLH1 intron 7. The insertion was further characterized as an AluSx-like element with ~115 bp in length. Functional studies demonstrated that the AluSx-like element led to complete disruption of mRNA splicing and probably resulted in transcriptional termination at the poly (A) region of the AluSx-like insertion.

Conclusions: The insertion of a truncated AluSx like element into MLH1 intron 7 results in aberrant splicing and transcription, thereby causing Lynch syndrome. This study confirms that retrotransposon insertions may be an important mechanism for cancer predisposition.
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http://dx.doi.org/10.1002/mgg3.1523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767547PMC
December 2020

Indications for Total Gastrectomy in CDH1 Mutation Carriers and Outcomes of Risk-Reducing Minimally Invasive and Open Gastrectomies.

JAMA Surg 2020 11;155(11):1050-1057

Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: CDH1 variants are increasingly identified on commercially available multigene panel tests, calling for data to inform counseling of individuals without a family history of gastric cancer.

Objectives: To assess association between CDH1 variant pathogenicity or family history of gastric or lobular breast cancer and identification of signet ring cell cancer and to describe outcomes of risk-reducing minimally invasive and open total gastrectomy.

Design, Setting, And Participants: This cohort study was performed from January 1, 2006, to January 1, 2020, in 181 patients with CDH1 germline variants from a single institution.

Interventions: Genetic counseling, esophagogastroduodenoscopy, and possible total gastrectomy.

Main Outcomes And Measures: CDH1 variant classification, family cancer history, findings of signet ring cell carcinoma at esophagogastroduodenoscopy and surgery, postoperative events and weight changes, and follow-up.

Results: Of 181 individuals with CDH1 germline variants (mean [SD] age at time of testing, 44 [15] years; 126 [70%] female), 165 harbored a pathogenic or likely pathogenic variant. Of these patients, 101 underwent open (n = 58) or minimally invasive (n = 43) total gastrectomy. Anastomotic leaks that required drainage were infrequent (n = 3), and median long-term weight loss was 20% (interquartile range [IQR], 10%-23%). In those undergoing minimally invasive operations, more lymph nodes were retrieved (median, 28 [IQR, 20-34] vs 15 [IQR, 9-19]; P < .001) and the hospital stay was 1 day shorter (median, 6 [IQR, 5-7] vs 7 [IQR, 6-7] days; P = .04). Signet ring cell cancer was identified in the surgical specimens of 85 of 95 patients (89%) with a family history of gastric cancer and 4 of 6 patients (67%) who lacked a family history. Among the latter 6 patients, 4 had a personal or family history of lobular breast cancer, including 2 with signet ring cell cancer. Of the 16 patients with pathogenic or likely pathogenic CDH1 variants who presented with locally advanced or metastatic gastric cancer, 3 (19%) had no family history of gastric cancer or personal or family history of lobular breast cancer.

Conclusions And Relevance: Total gastrectomy may be warranted for patients with pathogenic or likely pathogenic CDH1 variants and a family history of gastric or lobular breast cancer and may be appropriate for those without a family history. A minimally invasive approach is feasible and may be preferred for selected patients.
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http://dx.doi.org/10.1001/jamasurg.2020.3356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527942PMC
November 2020

Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy.

Clin Cancer Res 2020 07 6;26(13):3271-3279. Epub 2020 Mar 6.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Evaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.

Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity.

Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline and mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (, 57% vs 36%; , 17% vs 9%; < 0.003).

Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348681PMC
July 2020

An Emerging Paradigm for Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice: A Review.

JAMA Oncol 2020 05;6(5):764-771

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm with a rising incidence and is a leading public health challenge. Pancreatic ductal adenocarcinoma has been well characterized genomically, with findings of therapeutic actionability that have substantive implications for clinical practice based on recent high-level evidence.

Observations: Pathogenic germline alterations (PGAs) are relatively common in individuals with PDAC, as evidenced in multiple recent data sets, with a frequency of approximately 10%. The most common PGAs are in BRCA1, BRCA2, and ATM and more rarely in PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53, among others, with an aggregate frequency of 3.8% to 9.7%. These PGAs are of key interest owing to therapeutic actionability and the downstream identification of at-risk family members and possible hereditary cancer syndromes. Approximately 3% to 7% of individuals with PDAC harbor a BRCA1 or BRCA2 mutation, which are among the most frequently mutated genes in PDAC. Recent updates to the American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines recommend risk assessment for all individuals with PDAC irrespective of personal or family history or ethnicity. Treatment implications include the use of checkpoint inhibitor therapy for mismatch repair-deficient PDAC and the validation of poly-ADP (adenosine diphosphate)-ribose polymerase inhibitor (PARPi) therapy as a maintenance strategy in platinum-sensitive PDAC.

Conclusions And Relevance: With increasing evidence and slow improvement of outcomes, PDAC has entered the era of precision medicine. Germline mutations have been identified in key genes with an aggregate frequency of 3.8% to 9.7%, several of which are therapeutically actionable with platinum, PARPi, and checkpoint inhibitor therapy. Potential therapeutic targets need to be actively sought and identified.
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http://dx.doi.org/10.1001/jamaoncol.2019.5963DOI Listing
May 2020

A Multi-Institutional Cohort of Therapy-Associated Polyposis in Childhood and Young Adulthood Cancer Survivors.

Cancer Prev Res (Phila) 2020 03 12;13(3):291-298. Epub 2020 Feb 12.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20-33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair-deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060102PMC
March 2020

Risk of Metachronous Colorectal Neoplasm after a Segmental Colectomy in Lynch Syndrome Patients According to Mismatch Repair Gene Status.

J Am Coll Surg 2020 04 30;230(4):669-675. Epub 2020 Jan 30.

Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Background: Because of increased risk of metachronous colorectal cancer (CRC), all patients with Lynch syndrome (LS) are offered a total colectomy. However, because metachronous CRC rate by mismatch repair (MMR) gene is uncertain, and total colectomy negatively impacts quality of life, it remains unclear whether segmental resection is indicated for lower penetrance MMR genes. We evaluated metachronous CRC incidence according to MMR gene in LS patients who underwent a segmental colectomy.

Study Design: Single-center, retrospective cohort study in patients with an earlier colectomy for CRC and an MMR germline mutation in MLH1, MSH2, MSH6, or PMS2 followed prospectively in a hereditary CRC family registry. All patients underwent surveillance colonoscopy. Metachronous CRC was defined as one detected more than 1 year after index resection. Primary end point was cumulative incidence of metachronous CRC overall and by MMR gene.

Results: One hundred and ten patients were included: 35 with MLH1 likely pathogenic/pathogenic (LP/P) variants (32%), 42 MSH2 (38%), 20 MSH6 (18%), and 13 PMS2 (12%). Median follow-up 4.26 years (range 0.53 to 19.92 years). Overall, metachronous CRC developed in 22 patients (20%). At 10-year follow-up, incidence was 12% (95% CI 6% to 23%), with no metachronous CRC detected in patients with a PMS2 or MSH6 LP/P variant.

Conclusions: After index segmental resection, metachronous CRC is less likely to develop in LS patients with MSH6 or PMS2 LP/P variant than in MLH1 or MSH2 carriers. Our data support segmental resection and long-term colonoscopic surveillance rather than total colectomy in carefully selected, well-informed LS patients with MSH6 or PMS2 LP/P variant.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104918PMC
April 2020

Patients' Medical and Psychosocial Experiences After Detection of a Variant With Multigene Panel Testing.

JCO Precis Oncol 2019 28;3. Epub 2019 Mar 28.

University of Pennsylvania, Philadelphia, PA.

Purpose: Germline pathogenic variants (PV) are associated with hereditary diffuse gastric cancer and lobular breast cancer. Although prevalence of PV is low in the general population, detection of these variants is increasing with the growing use of multigene panel testing. Little is known about the experiences of individuals tested for variants in the multigene panel testing era.

Methods: Participants recruited from the Prospective Registry of Multiplex Testing completed a cross-sectional self-report survey regarding genetic testing experiences, medical management, and psychosocial adaptation.

Results: Discordance existed in interpretations of results; 13.3% of cases had disagreements in variant classifications among commercial laboratories, and 21.4% had disagreements between participant self-report and ClinVar classification. Survey data were available from 57 individuals reporting either PV (n = 16) or variants of uncertain significance (VUS; n = 41). Those with PV were more likely than those with VUS to report receiving a recommendation for prophylactic gastrectomy, although only 40.0% of those with PV received this recommendation. Participants with VUS were less satisfied with their health care providers' knowledge and reported less knowledge, distress, and worry about discrimination. Participants with PV perceived greater breast cancer risks, but similar gastric cancer risks, as those with VUS.

Conclusion: Few individuals with PV report receiving recommendations for prophylactic gastrectomy, and no differences in perceived gastric cancer risk were observed based on participants' results, suggesting serious unmet informational needs.
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http://dx.doi.org/10.1200/PO.18.00300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738946PMC
March 2019

Outcome of Pancreatic Cancer Surveillance Among High-Risk Individuals Tested for Germline Mutations in and .

Cancer Prev Res (Phila) 2019 09 23;12(9):599-608. Epub 2019 Jul 23.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Germline mutations in are risk factors for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether results of surveillance for PDAC in high risk individuals (HRI) differ between those with and without a pathogenic mutation. This prospective study was conducted within the Pancreatic Tumor Registry at a major cancer center. There were 83 HRIs with ≥1 first-degree relative with PDAC who underwent surveillance and testing for pathogenic germline mutations in A secondary analysis includes 18 HRIs with known mutations in but with weaker family history. HRIs were evaluated over time using magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound when indicated by MRCP findings. We reviewed imaging results, blinded to mutation status. Demographic information was obtained from interviewer-administered questionnaires. The outcome was the proportion with any pancreatic abnormality identified at initial or follow-up surveillance. Among the 83 HRIs in the main analysis, 48 had a mutation in and 35 did not. Overall, 16 of 48 (33%) -positive and 13 of 35 (37%) -negative participants had pancreatic abnormalities on imaging; in each group, all but one finding was an intraductal papillary mucinous neoplasm. Among those with pathogenic mutations but weaker family history, results were similar: 7 of 18 (39%) with pancreatic abnormalities. Results of surveillance for pancreatic abnormalities on imaging are similar regardless of mutation status. While the results from this small study need confirmation in other studies, at present there does not appear to be increased yield from targeting individuals with mutations for surveillance.
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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726560PMC
September 2019

Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.

J Natl Cancer Inst 2018 10;110(10):1067-1074

Department of Medicine.

Background: Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications.

Methods: Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves.

Results: PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2.

Conclusions: PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.
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http://dx.doi.org/10.1093/jnci/djy024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186514PMC
October 2018

Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations.

Clin Cancer Res 2018 03 24;24(6):1326-1336. Epub 2018 Jan 24.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC. Archival and prospectively acquired samples and matched normal DNA from = 833 PDAC cases were analyzed using a hybridization capture-based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341 to 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Available germline testing, IHC, and microsatellite instability (MSI) PCR results were reviewed to assess and confirm MMR-D and MSI status. MMR-D in PDAC is a rare event among PDAC patients (7/833), occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load, and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response, 2 partial responses, 1 stable disease). An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856632PMC
March 2018

Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

Cancer 2018 04 16;124(7):1374-1382. Epub 2018 Jan 16.

Memorial Sloan Kettering Cancer Center, New York, New York.

Background: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival.

Methods: Gemcitabine and cisplatin were dosed at 600 and 25 mg/m , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]).

Results: Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months).

Conclusions: The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867226PMC
April 2018

Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma.

Eur J Cancer 2018 01 8;89:19-26. Epub 2017 Dec 8.

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address:

Purpose: BRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC).

Methods: Patients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1-2 lines of treatment, Eastern Cooperative Oncology Group 0-2, were enrolled. Veliparib was dosed at a volume of 300 mg twice-daily (N = 3), then 400 mg twice-daily (N = 15) days 1-28. The primary end-point was to determine the response rate of veliparib; secondary end-points included progression-free survival (PFS), duration of response, overall survival (OS) and safety.

Results: Sixteen patients were enrolled; male N = 8 (50%). Median age was 52 years (range 43-77). Five (31%) had a BRCA1 and 11 (69%) had a BRCA2 mutation. Fourteen (88%) patients had received prior platinum-based therapy. No confirmed partial responses (PRs) were seen: one (6%) unconfirmed PR was observed at 4 months with disease progression (PD) at 6 months; four (25%) had stable disease (SD), whereas 11 (69%) had PD as best response including one with clinical PD. Median PFS was 1.7 months (95% confidence interval [CI] 1.57-1.83) and median OS was 3.1 months (95% CI 1.9-4.1). Six (38%) patients had grade III toxicity, including fatigue (N = 3), haematology (N = 2) and nausea (N = 1).

Conclusions: Veliparib was well tolerated, but no confirmed response was observed although four (25%) patients remained on study with SD for ≥ 4 months. Additional strategies in this population are needed, and ongoing trials are evaluating PARPis combined with chemotherapy (NCT01585805) and as a maintenance strategy (NCT02184195).
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http://dx.doi.org/10.1016/j.ejca.2017.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351022PMC
January 2018

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

JAMA 2017 09;318(9):825-835

Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention.

Objective: To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines.

Design, Setting, And Participants: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017.

Exposure: Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines.

Main Outcomes And Measures: Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing.

Results: Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing.

Conclusions And Relevance: In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study.

Trial Registration: clinicaltrials.gov Identifier: NCT01775072.
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http://dx.doi.org/10.1001/jama.2017.11137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611881PMC
September 2017

Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

Fam Cancer 2018 01;17(1):71-77

Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave., Box 295, New York, NY, 10065, USA.

Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.
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http://dx.doi.org/10.1007/s10689-017-0006-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708147PMC
January 2018

Psychosocial factors associated with the uptake of contralateral prophylactic mastectomy among BRCA1/2 mutation noncarriers with newly diagnosed breast cancer.

Breast Cancer Res Treat 2017 04 1;162(2):297-306. Epub 2017 Feb 1.

Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Women who are newly diagnosed with breast cancer may consider contralateral prophylactic mastectomy (CPM) to reduce their future risk of cancer in their unaffected breast. Pre-surgical BRCA1/2 genetic testing can provide valuable risk information to guide this choice. However, little is understood about why BRCA1/2 mutation noncarriers, who are generally not at substantially elevated risk of contralateral disease, select CPM.

Methods: We examined the uptake of CPM among breast cancer patients identified as BRCA1/2 mutation noncarriers (n = 92) as part of a larger prospective study of the impact of pre-surgical BRCA1/2 testing. Data obtained from self-report questionnaires and patient medical records were used to examine associations between theoretically relevant background and psychosocial factors and BRCA1/2 mutation noncarriers' decisions to undergo CPM.

Results: Among BRCA1/2 mutation noncarriers, 25% (n = 23) elected to undergo CPM. Psychosocial factors including a self-reported physician recommendation for CPM, greater perceived contralateral breast cancer risk, and greater perceived benefits of CPM were all significantly associated with the uptake of CPM.

Conclusions: A sizeable minority of BRCA1/2 mutation noncarriers choose to undergo CPM after learning their mutation status through pre-surgical genetic testing. BRCA1/2 mutation noncarriers' cognitive perceptions and social influences appear to be important in shaping their decisions regarding CPM. This work highlights the importance of several psychosocial factors in influencing patients' surgical decisions. Future research is needed that examines the formation of BRCA1/2 mutation noncarriers' beliefs regarding their disease and available treatment options, and that characterizes the physician-patient communication that occurs in this complex decision-making context.
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http://dx.doi.org/10.1007/s10549-017-4123-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329117PMC
April 2017

CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site.

PLoS One 2016 23;11(11):e0165654. Epub 2016 Nov 23.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Disease-causing germline mutations in CDH1 cause Hereditary Diffuse Gastric Cancer (HDGC). For patients who meet the HDGC screening criteria, the identification and classification of the sequence variants found in CDH1 are critical for risk management of patients. In this report, we describe a germline CDH1 c.1679C>G (p.T560R) variant identified in a 50 year old man who was diagnosed with gastric cancer with a strong family history of gastric cancer (one living brother was diagnosed with gastric cancer at 63 and another brother died of gastric cancer at 45). cDNA analysis, involving fragment analysis and cloning, indicated that the p.T560R mutation created a novel 5' splice donor site, which led to a novel transcript with a 32 nucleotide deletion in exon 11. This abnormal transcript putatively produces a truncated CDH1 protein (E-cadherin) of 575 amino acids instead of 882. We also demonstrated that the variant completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Furthermore, the CDH1 c.1679C>G (p.T560R) variant segregated with gastric cancer in all three family members affected with gastric cancer in this family. These results support the conclusion that CDH1 c.1679C>G (p.T560R) variant is a pathogenic mutation and contributes to HDGC through disruption of normal splicing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120775PMC
June 2017

Total Gastrectomy for Hereditary Diffuse Gastric Cancer at a Single Center: Postsurgical Outcomes in 41 Patients.

Ann Surg 2017 12;266(6):1006-1012

*Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY †Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY §Department of Gastroenterology, Memorial Sloan Kettering Cancer Center, New York, NY ¶Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Objective: The aim of this study was to describe postoperative outcomes of total gastrectomy at our institution for patients with hereditary diffuse gastric cancer (HDGC).

Background: HDGC, which is mainly caused by germline mutations in the E-cadherin gene (CDH1), renders a lifetime risk of gastric cancer of up to 70%, prompting a recommendation for prophylactic total gastrectomy.

Methods: A prospective gastric cancer database identified 41 patients with CDH1 mutation who underwent total gastrectomy during 2005 to 2015. Perioperative, histopathologic, and long-term data were collected.

Results: Of the 41 patients undergoing total gastrectomy, median age was 47 years (range 20 to 71). There were 14 men and 27 women, with 25 open operations and 16 minimally invasive operations. Median length of stay was 7 days (range 4 to 50). In total, 11 patients (27%) experienced a complication requiring intervention, and there was 1 peri-operative mortality (2.5%). Thirty-five patients (85%) demonstrated 1 or more foci of intramucosal signet ring cell gastric cancer in the examined specimen. At 16 months median follow-up, the median weight loss was 4.7 kg (15% of preoperative weight). By 6 to 12 months postoperatively, weight patterns stabilized. Overall outcome was reported to be "as expected" by 40% of patients and "better than expected" by 45%. Patient-reported outcomes were similar to those of other patients undergoing total gastrectomy.

Conclusion: Total gastrectomy should be considered for all CDH1 mutation carriers because of the high risk of invasive diffuse-type gastric cancer and lack of reliable surveillance options. Although most patients have durable weight loss after total gastrectomy, weights stabilize at about 6 to 12 months postoperatively, and patients report outcomes as being good to better than their preoperative expectations. No patients have developed gastric cancer recurrence after resections.
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http://dx.doi.org/10.1097/SLA.0000000000002030DOI Listing
December 2017

Educational and Psychosocial Support Needs in Lynch Syndrome: Implementation and Assessment of an Educational Workshop and Support Group.

J Genet Couns 2017 Apr 12;26(2):232-243. Epub 2016 Oct 12.

Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 295, New York, NY, 10065, USA.

Few reports of educational and counseling support resources exist for Lynch syndrome (LS), a disorder requiring multi-organ cancer screening and specialized medical care throughout adult life. Here we describe the development and efficacy of two resources designed to address this need, the Memorial Sloan Kettering Cancer Center Clinical Genetics Service annual Lynch Syndrome Educational Workshop (LSEW), and a quarterly Lynch Syndrome Patient Advocacy Network (LSPAN) support group. The LSEW and LSPAN were implemented beginning in 2012. Participant survey data evaluating satisfaction, clarity, and unmet needs for each event were retrospectively analyzed and summarized using descriptive statistics. Annual LSEW attendance ranged from 53 to 75 total participants. LSEW year 1 participants indicated a need for a support group, and preferred in-person meetings at a frequency of every 3-6 months. For LSEW year 2-5 participants, >96 % reported satisfaction with the LSEW, and >82 % expressed interest in secure online support. Common themes for improvement included increased time for question and answer sessions and additional introductory genetics education. Responding LSPAN participants (n = 57 total survey responses in 11 meetings) found the meetings helpful (100 %), information clear (91 %), and presence of a genetic counselor useful (67 %). Desired discussion topics included coping with stress and anxiety, development of a support network, family communication about LS, genetic testing decisions, and bereavement. Following genetic counseling, a need exists for ongoing educational and emotional support in LS. Implementation of resources such as the LSEW and LSPAN is feasible and perceived as helpful by participants.
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http://dx.doi.org/10.1007/s10897-016-0015-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383525PMC
April 2017

Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels.

J Clin Oncol 2016 06 28;34(18):2141-7. Epub 2016 Mar 28.

Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy.

Purpose: Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load.

Methods: We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry.

Results: Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0).

Conclusion: A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping.
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http://dx.doi.org/10.1200/JCO.2015.65.1067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962706PMC
June 2016

Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.

Expert Rev Gastroenterol Hepatol 2016 Aug 26;10(8):893-905. Epub 2016 Feb 26.

b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.

Pancreatic cancer is one of the most challenging cancers. Whole genome sequencing studies have been conducted to elucidate the underlying fundamentals underscoring disease behavior. Studies have identified a subgroup of pancreatic cancer patients with distinct molecular and clinical features. Genetic fingerprinting of these tumors is consistent with an unstable genome and defective DNA repair pathways, which creates unique susceptibility to agents inducing DNA damage. BRCA1/2 mutations, both germline and somatic, which lead to impaired DNA repair, are found to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Recent studies have elucidated that PARP inhibitors and platinum agents may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. In this review we discuss the characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as a novel treatment approach.
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http://dx.doi.org/10.1586/17474124.2016.1153424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988832PMC
August 2016

Identification of germline genetic mutations in patients with pancreatic cancer.

Cancer 2015 Dec 6;121(24):4382-8. Epub 2015 Oct 6.

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.

Background: Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC.

Methods: A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated.

Results: Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation).

Conclusions: Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation.
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http://dx.doi.org/10.1002/cncr.29664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193099PMC
December 2015

Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families.

Breast Cancer Res Treat 2014 Jun 14;145(3):625-34. Epub 2014 May 14.

Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.

BRCA1/2 large rearrangement (LR) testing has been available to patients since 2006. Three existing models commonly used in cancer genetics clinical and research settings (BRCAPRO, Penn II and Myriad II) have not been assessed for their performance in predicting the presence of BRCA1/2 large genomic rearrangements in patients who do not have mutations detectable by the traditional Sanger sequencing approach. This study sought to determine if there is an optimal pre-test probability "cut off" value, calculated using these models, to optimize detection of large rearrangements (LRs). Our cohort consisted of 3,301 probands seen for genetic counseling and BRCA1/2 clinical testing from September 2006 to September 2011. A detailed personal and three-generation family history, including self-reported ethnicity, was taken as part of our standard clinical practice. We applied the BRCAPRO, Penn II, and Myriad II models to the probands with LRs. In our cohort of 3,301 probands, 150 carried a non-Ashkenazi mutation in BRCA1 or BRCA2. Seventeen unrelated probands carried a private BRCA1/2 LR (17/150, 11.3 % of all detectable non-AJ mutations). At a pre-test probability cutoff of 10 %, all three empiric risk models would have failed to identify almost 30 % of probands with LRs. Our study shows that BRCA1/2 LR testing should be offered to all women who meet criteria for BRCA1/2 sequence analysis.
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http://dx.doi.org/10.1007/s10549-014-2987-6DOI Listing
June 2014

Mosaic partial deletion of the PTEN gene in a patient with Cowden syndrome.

Fam Cancer 2014 Sep;13(3):459-67

Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 295, New York, NY, 10065, USA.

Cowden syndrome is an autosomal dominant condition caused by pathogenic mutations in the phosphatase and tensin homolog (PTEN) gene. Only a small proportion of identified pathogenic mutations have been reported to be large deletions and rearrangements. We report on a female patient with a previous history of breast ductal carcinoma in situ who presented to our institution for management of gastrointestinal hamartomatous polyposis. Although several neoplastic predisposition syndromes were considered, genetic evaluation determined that the patient met clinical diagnostic criteria for Cowden syndrome. Array-based comparative genomic hybridization was performed and revealed a mosaic partial deletion of the PTEN gene. Follow-up clinical history including bilateral thyroid nodules, dermatological findings, and a new primary "triple-negative" adenocarcinoma of the contralateral breast are discussed. We highlight the need for recognition and awareness of mosaicism as it may provide an explanation for variable phenotypic presentations and may alter the genetic counseling risk assessment of affected individuals and family members.
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http://dx.doi.org/10.1007/s10689-014-9709-4DOI Listing
September 2014

The genetic counselor: an important surgical ally in the optimal care of the cancer patient.

Adv Surg 2012 ;46:137-53

Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 295, New York, NY 10065, USA.

Genetic counselors and surgeons both have important roles in the care of patients with hereditary cancer predisposition syndromes. Surgeons have the initial responsibility to identify and refer high-risk patients. Genetic counselors' specialized skill sets are then used in the risk assessment and genetic evaluation of such patients and their at-risk family members, and this may be performed in multiple settings. As discussed in this article, these roles and the processes of genetic counseling and genetic testing may be enhanced through multiple surgeon and genetic counselor collaborations. Continued medical management of patients and families with hereditary cancer predisposition syndromes becomes the responsibility of patients and their multiple health care providers. Box 7 provides a list of resources to assist in finding a local genetic counselor. Because there are various opportunities for surgeons and genetic counselors to collaborate, the authors urge surgeons to recognize the importance of, identify, and work in partnership with a local genetic counselor because that relationship sets the stage for optimal care of the cancer patient.
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http://dx.doi.org/10.1016/j.yasu.2012.03.010DOI Listing
August 2012

Juvenile polyposis syndrome presenting with familial gastric cancer and massive gastric polyposis.

J Clin Oncol 2012 Sep 23;30(25):e229-32. Epub 2012 Jul 23.

Memorial Sloan-Kettering Cancer Center, Box 295, 1275 York Ave, New York, NY 10065, USA.

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http://dx.doi.org/10.1200/JCO.2012.41.7949DOI Listing
September 2012

The prevalence of thyroid cancer and benign thyroid disease in patients with familial adenomatous polyposis may be higher than previously recognized.

Clin Colorectal Cancer 2012 Dec 15;11(4):304-8. Epub 2012 Mar 15.

Department of Surgery, Colorectal Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Purpose: Patients with familial adenomatous polyposis (FAP) are at increased risk for colorectal cancer and extracolonic neoplasms. The prevalence of thyroid cancer (TC) and benign thyroid disease in this patient population is unclear, and guidelines for screening for TC in these patients are not well established. The purpose of this study was to report the prevalence of TC and benign thyroid disease in patients with FAP.

Methods: The prospectively maintained Hereditary Colorectal Cancer Family Registry at Memorial Sloan-Kettering Cancer Center was queried to identify patients with FAP and with TC and/or benign thyroid disease.

Results: Sixty-six patients with FAP were identified. There were 30 men and 36 women, with a median age of 38.6 years. Four (6.1%) patients had a history of TC. All were women, with a mean age at TC diagnosis of 36.5 years. Three of the 4 TCs were papillary thyroid cancer. Two patients with TC presented with palpable nodules. An additional 6 (9.1%) patients with FAP had a history of benign thyroid disease, including nodules (3), hypothyroidism (2), cysts (2), goiter (1), and thyroiditis (1). Three of 4 patients with TC and all 6 patients with benign thyroid disease had other extracolonic manifestations associated with FAP.

Conclusions: The prevalences of TC (6.1%) and benign thyroid disease (9.1%) are increased in our patients with FAP and are higher than noted in some previous reports. Periodic thyroid ultrasound screening should be considered in patients with FAP to further elucidate the prevalence and for possible early detection of TC and benign thyroid disease in this population.
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http://dx.doi.org/10.1016/j.clcc.2012.01.006DOI Listing
December 2012