Publications by authors named "Gregory E Idos"

18 Publications

  • Page 1 of 1

Bridging the Gap: Patient Navigation Increases Colonoscopy Follow-up After Abnormal FIT.

Clin Transl Gastroenterol 2021 02 22;12(2):e00307. Epub 2021 Feb 22.

Los Angeles County Department of Health Services, Los Angeles, California, USA.

Introduction: Recent studies indicate low rates of follow-up colonoscopy after abnormal fecal immunochemical testing (FIT) within safety net health systems. A patient navigation (PN) program is an evidence-based strategy that has been shown to improve colonoscopy completion in private and public healthcare settings. The aim of this study was to evaluate the effectiveness of a PN program to encourage follow-up colonoscopy after abnormal FIT within a large safety net hospital system.

Methods: We established an enterprisewide PN program at 5 tertiary care hospitals within the Los Angeles County Department of Health Services system in 2018. The PN assisted adult patients aged 50-75 years with an abnormal FIT to a follow-up colonoscopy within 6 months. PN activities included initiating referral for and scheduling of colonoscopy, performing reminder phone calls to patient for their upcoming colonoscopy, and following up with patients who did not attend their colonoscopy. We assess the effectiveness of the PN intervention by comparing follow-up colonoscopy rates with a period before the intervention.

Results: There were 2,531 patients with abnormal FIT results (n = 1,214 in 2017 and n = 1,317 in 2018). A majority were women (55% in 2017 vs 52% in 2018) with a mean age of 60 ± 6.2 years. From a previous mean of 163 days without PN in 2017, the mean time from abnormal FIT to colonoscopy with PN improved to 113 days in 2018. The frequency of colonoscopy completion with PN increased from 40.6% (n = 493) in 2017 to 46% (n = 600) in 2018.

Discussion: After the introduction of the PN program, there was a significant increase in patients undergoing follow-up colonoscopy after abnormal FIT and patients were more likely to undergo colonoscopy within the recommended 6 months.
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http://dx.doi.org/10.14309/ctg.0000000000000307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901799PMC
February 2021

Psychosocial outcomes following germline multigene panel testing in an ethnically and economically diverse cohort of patients.

Cancer 2021 Apr 15;127(8):1275-1285. Epub 2020 Dec 15.

Center for Precision Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.

Background: Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate-risk pathogenic variants (PVs).

Methods: Study participants (N = 1264) were counseled and tested with a 25- or 28-gene panel and completed a 3-month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA).

Results: The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non-Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non-English-speaking. The genetic test results were as follows: 7% had a high-risk PV, 6% had a moderate-risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of "never," "rarely," or only "sometimes" reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high- and moderate-risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High- and moderate-risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences.

Conclusions: In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds.

Lay Summary: Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate-risk pathogenic variants (mutations) and among carriers of variants of uncertain significance. This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% "never," "rarely," or only "sometimes" reacted negatively to results. Somewhat higher uncertainty and distress were identified among carriers of high- and moderate-risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result. Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results.
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http://dx.doi.org/10.1002/cncr.33357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058169PMC
April 2021

Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells.

Gynecol Oncol 2020 12 5;159(3):869-876. Epub 2020 Oct 5.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, and Beckman Research Institute, Duarte, CA, USA; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.

Objective: Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity.

Methods: We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices.

Results: BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality.

Conclusions: BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.040DOI Listing
December 2020

Lymphocytic infiltration in stage II microsatellite stable colorectal tumors: A retrospective prognosis biomarker analysis.

PLoS Med 2020 09 24;17(9):e1003292. Epub 2020 Sep 24.

Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.

Background: Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable.

Methods And Findings: We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016).

Limitations: This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival.

Conclusion: Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.
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http://dx.doi.org/10.1371/journal.pmed.1003292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514069PMC
September 2020

Pre-Procedural COVID Testing: The "New Normal".

Gastroenterology 2021 05 1;160(6):2189-2190. Epub 2020 Jul 1.

Division of Gastroenterology, Department of Medicine, City of Hope Medical Center, Duarte, California.

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http://dx.doi.org/10.1053/j.gastro.2020.06.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328632PMC
May 2021

The Prognostic Implications of Tumor Infiltrating Lymphocytes in Colorectal Cancer: A Systematic Review and Meta-Analysis.

Sci Rep 2020 02 25;10(1):3360. Epub 2020 Feb 25.

University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

Tumor-infiltrating lymphocytes (TILs) are an important histopathologic feature of colorectal cancer that confer prognostic information. Previous clinical and epidemiologic studies have found that the presence and quantification of tumor-infiltrating lymphocytes are significantly associated with disease-specific and overall survival in colorectal cancer. We performed a systematic review and meta-analysis, establishing pooled estimates for survival outcomes based on the presence of TILs in colon cancer. PubMed (Medline), Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to April 2017. Studies were included, in which the prognostic significance of intratumoral tumor infiltrating lymphocytes, as well as subsets of CD3, CD8, FOXP3, CD45R0 lymphocytes, were determined within the solid tumor center, the invasive margin, and tumor stroma. Random-effects models were calculated to estimated summary effects using hazard ratios. Forty-three relevant studies describing 21,015 patients were included in our meta-analysis. The results demonstrate that high levels of generalized TILS as compared to low levels had an improved overall survival (OS) with a HR of 0.65 (p = <0.01). In addition, histologically localized CD3+ T-cells at the tumor center were significantly associated with better disease-free survival (HR = 0.46, 95% CI 0.36-0.61, p = 0.05), and CD3 + cells at the invasive margin were associated with improved disease-free survival (HR = 0.57, 95% CI 0.38-0.86, p = 0.05). CD8+ T-cells at the tumor center had statistically significant prognostic value on cancer-specific survival and overall survival with HRs of 0.65 (p = 0.02) and 0.71 (p < 0.01), respectively. Lastly, FOXP3+ T-cells at the tumor center were associated with improved prognosis for cancer-specific survival (HR = 0.65, p < 0.01) and overall survival (HR = 0.70, p < 0.01). These findings suggest that TILs and specific TIL subsets serve as prognostic biomarkers for colorectal cancer.
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http://dx.doi.org/10.1038/s41598-020-60255-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042281PMC
February 2020

A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice.

Nat Commun 2019 12 12;10(1):5681. Epub 2019 Dec 12.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.

Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAG. To investigate the role of UVRAG in vivo, we generated mutant mice that inducibly express UVRAG (iUVRAG). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAG mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAG mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.
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http://dx.doi.org/10.1038/s41467-019-13475-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908726PMC
December 2019

Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk.

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

University of Southern California, Los Angeles, CA.

Purpose: Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations.

Patients And Methods: This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics-University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute-who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate).

Results: Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% 41%; < .001) to encourage their relatives to be tested.

Conclusion: In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results.
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http://dx.doi.org/10.1200/PO.18.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260917PMC
March 2019

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

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

Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.

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

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

J Natl Cancer Inst 2019 02;111(2):146-157

Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA.

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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http://dx.doi.org/10.1093/jnci/djy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555904PMC
February 2019

Patient communication of cancer genetic test results in a diverse population.

Transl Behav Med 2018 01;8(1):85-94

USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

Research on the communication of genetic test results has focused predominately on non-Hispanic White (NHW) mutation-positive families with high-risk hereditary cancer conditions. Little is known about this process for racially and ethnically diverse individuals or for those with mutations in moderate risk genes. The communication behaviors of study participants who carry a gene mutation were analyzed 3 months after disclosure of genetic test results. Participants were queried about communication of their results, as part of a prospective study of multi-gene panel genetic testing. The responses of particpants who tested positive were analyzed by race/ethnicity and by level of cancer risk (high vs. moderate). Of the 216 mutation-positive study participants, 136 (63%) responded. Self-reported race/ethnicity was 46% NHW, 41% Hispanic, 10% Asian, and 2% Black. The majority (99.0%, n = 135) had shared their results with someone and 96% had told a family member (n = 130). Hispanic respondents were less likely to have told a healthcare provider about their results than NHW (29% vs. 68%, p < .0001). Asian respondents were less likely than NHW to encourage family members to undergo testing (OR = 0.1, p = .03); but Asian family members were more likely to undergo testing (OR = 8.0, p = .03). There were no differences in communication between those with a mutation in a high- or moderate-risk gene. Three months post genetic testing, communication of results was very high; 30% reported a family member underwent genetic testing. Further studies are needed to better understand the communication process in individuals from diverse racial/ethnic backgrounds.
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http://dx.doi.org/10.1093/tbm/ibx010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065549PMC
January 2018

Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort.

Cancer Genet 2016 Apr 12;209(4):130-7. Epub 2016 Jan 12.

USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; Department of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.

This study aims to assess multi-gene panel testing in an ethnically diverse clinical cancer genetics practice. We conducted a retrospective study of individuals with a personal or family history of cancer undergoing clinically indicated multi-gene panel tests of 6-110 genes, from six commercial laboratories. The 475 patients in the study included 228 Hispanics (47.6%), 166 non-Hispanic Whites (35.4%), 55 Asians (11.6%), 19 Blacks (4.0%), and seven others (1.5%). Panel testing found that 15.6% (74/475) of patients carried deleterious mutations for a total of 79 mutations identified. This included 7.4% (35/475) of patients who had a mutation identified that would not have been tested with a gene-by-gene approach. The identification of a panel-added mutation impacted clinical management for most of cases (69%, 24/35), and genetic testing was recommended for the first degree relatives of nearly all of them (91%, 32/35). Variants of uncertain significance (VUSs) were identified in a higher proportion of tests performed in ethnic minorities. Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment. VUSs represent an interpretive challenge due to less data available outside of White, non-Hispanic populations. Further studies are necessary to expand understanding of the implementation and utilization of panels across broad clinical settings and patient populations.
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http://dx.doi.org/10.1016/j.cancergen.2015.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835267PMC
April 2016

A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

Cancer Genet 2016 Mar 22;209(3):75-81. Epub 2015 Dec 22.

USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. Electronic address:

Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.
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http://dx.doi.org/10.1016/j.cancergen.2015.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447287PMC
March 2016

Genome-wide association study of colorectal cancer identifies six new susceptibility loci.

Nat Commun 2015 Jul 7;6:7138. Epub 2015 Jul 7.

Harvard Medical School, Boston, Massachusetts 02114, USA.

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.
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http://dx.doi.org/10.1038/ncomms8138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967357PMC
July 2015

Genetic markers of malignant transformation in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis.

Pancreas 2012 Nov;41(8):1195-205

Division of Gastroenterology and Hepatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objectives: The objective of this study was to determine the relationship between specific genetic alterations and malignant transformation in intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

Methods: Quantitative meta-analysis was conducted of studies through October 2010 that adhered to the 1996 World Health Organization guidelines for distinguishing adenoma and borderline IPMN versus carcinoma in surgically resected specimens using a random-effects model. We developed a 6-point scoring system to assess study quality.

Results: Thirty-nine studies (1235 IPMN samples) satisfied the inclusion criteria, and we conducted pooled analysis of 8 genetic markers: MUC1, MUC2, MUC5AC, kRas, p53, hTERT (human telomerase reverse transcriptase), cyclooxygenase 2, and Shh (Sonic hedgehog). Markers having the strongest association with malignant IPMN were hTERT (odds ratio [OR], 11.4; 95% confidence interval [CI], 3.5-36.7) and Shh (OR, 6.9; 95% CI, 2.4-20.2), whereas MUC5AC (OR, 1.0; 95% CI, 0.1-13.9) and kRas (OR, 2.0; 95% CI, 1.0-4.3) showed weak association with IPMN histologic progression.

Conclusions: Expression of hTERT is strongly associated with malignant transformation in IPMN, consistent with up-regulation of hTERT as a key step in progression of IPMN to cancer. Expression of kRas and MUC5AC is common but not strongly associated with IPMN histologic progression. The quality criteria used here may guide future reporting of genetic markers related to malignant transformation of IPMN.
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http://dx.doi.org/10.1097/MPA.0b013e3182580fb4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850028PMC
November 2012

RARbeta2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia.

Oncogene 2004 Oct;23(47):7846-53

Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem-cell disorder that leads to ineffective hematopoiesis, bone marrow fibrosis, and extramedullary hematopoiesis. The molecular mechanisms underlying the development of this myeloproliferative syndrome are currently unknown. In order to identify tumor suppressor genes that may be involved in the disease process, we performed an analysis for loss of heterozygosity (LOH) in CD34+ cells from 29 patients with MMM. We observed a frequency of allelic loss on chromosomal arm 3p in 24% of cases. Detailed mapping of 3p revealed a distinct region of deletion at 3p24. Among the genes known to map within this region is the retinoic acid receptor-beta (RARbeta2) gene. To determine whether RARbeta2 gene activity is diminished in this disease, we analysed its expression in CD34+ cells from 17 patients with MMM using quantitative PCR. Our results indicate that expression of RARbeta2 is significantly decreased in 100% of patient samples compared to that in CD34+ cells from 10 normal individuals. Since allelic loss at 3p24 occurs in <25% of patients, we investigated the contribution of epigenetic modifications to RARbeta2 inactivity. Using methylation-specific PCR, we found hypermethylation of RARbeta2 in 16 of 18 patients (89%), while the methylated form of the gene was absent in CD34+ cells from nine normal individuals. Our results suggest that RARbeta2 acts as a tumor suppressor gene in MMM and that epigenetic changes are the most significant determinants of RARbeta2 gene activity in these patients.
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http://dx.doi.org/10.1038/sj.onc.1207510DOI Listing
October 2004

Identification of interaction partners and substrates of the cyclin A1-CDK2 complex.

J Biol Chem 2004 Aug 24;279(32):33727-41. Epub 2004 May 24.

Department of Medicine, Hematology/Oncology, University of Münster, D-48129 Münster, Germany.

The CDK2-associated cyclin A1 is essential for spermatogenesis and contributes to leukemogenesis. The detailed molecular functions of cyclin A1 remain unclear, since the molecular networks involving cyclin A1-CDK2 have not been elucidated. Here, we identified novel cyclin A1/CDK2 interaction partners in a yeast triple-hybrid approach. Several novel proteins (INCA1, KARCA1, and PROCA1) as well as the known proteins GPS2 (G-protein pathway suppressor 2), Ku70, receptor for activated protein kinase C1/guanine nucleotide-binding protein beta-2-like-1, and mRNA-binding motif protein 4 were identified as interaction partners. These proteins link the cyclin A1-CDK2 complex to diverse cellular processes such as DNA repair, signaling, and splicing. Interactions were confirmed by GST pull-down assays and co-immunoprecipitation. We cloned and characterized the most frequently isolated unknown gene, which we named INCA1 (inhibitor of CDK interacting with cyclin A1). The nuclear INCA1 protein is evolutionarily conserved and lacks homology to any known gene. This novel protein and two other interacting partners served as substrates for the cyclin A1-CDK2 kinase complex. Cyclin A1 and all interaction partners were highly expressed in testis with varying degrees of tissue specificity. The highest expression levels were observed at different time points during testis maturation, whereas expression levels in germ cell cancers and infertile testes decreased. Taken together, we identified testicular interaction partners of the cyclin A1-CDK2 complex and studied their expression pattern in normal organs, testis development, and testicular malignancies. Thereby, we establish a new basis for future functional analyses of cyclin A1. We provide evidence that the cyclin A1-CDK2 complex plays a role in several signaling pathways important for cell cycle control and meiosis.
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http://dx.doi.org/10.1074/jbc.M401708200DOI Listing
August 2004
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