BRCA2 and predisposition to pancreatic and other cancers

Pancreatic adenocarcinoma is a major cause of cancer deaths in the industrialised world. Recent work has focused on the genetics of pancreatic cancer with a goal of finding an early detection marker that might allow for greater rates of survival than are currently possible. The breast cancer 2 gene (BRCA2) is one of numerous genes implicated in familial pancreatic cancer. Carriers of germline mutations of the BRCA2 gene have an increased risk of several cancers, among them pancreatic adenocarcinoma. During pancreatic carcinogenesis, bi-allelic inactivation of BRCA2 occurs as a late event, suggesting that other genetic events must occur before neoplastic cells can tolerate loss of BRCA2.

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Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion

Journal of Clinical Oncology ◽

10.1200/jco.18.01489 ◽

2019 ◽

Vol 37 (2) ◽

pp. 153-164 ◽

Cited By ~ 35

Author(s):

Elena M. Stoffel ◽

Shannon E. McKernin ◽

Randall Brand ◽

Marcia Canto ◽

Michael Goggins ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Pancreatic Adenocarcinoma ◽

Health Care Providers ◽

Expert Panel ◽

Familial Pancreatic Cancer ◽

Care Providers ◽

Increased Risk ◽

History Of

Purpose An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO’s membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members’ curated files. Provisional Clinical Opinion All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

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Characteristics of Pure Familial Pancreatic Cancer Families and Those with Additional Breast Cancer

Open Access Journal of Oncology and Medicine ◽

10.32474/oajom.2020.04.000178 ◽

2020 ◽

Vol 4 (1) ◽

Author(s):

Detlef K Bartsch

Keyword(s):

Breast Cancer ◽

Pancreatic Cancer ◽

Familial Pancreatic Cancer

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Correction: Management of patients with increased risk for familial pancreatic cancer: updated recommendations for the international cancer of the pancreas screening (CAPS) Consortium

Gut ◽

10.1136/gutjnl-2019-319352corr1 ◽

2020 ◽

Vol 69 (6) ◽

pp. e3-e3

Keyword(s):

Pancreatic Cancer ◽

Familial Pancreatic Cancer ◽

Cancer Of The Pancreas ◽

Increased Risk

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Genomic Features and Clinical Management of Patients with Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20030561 ◽

2019 ◽

Vol 20 (3) ◽

pp. 561 ◽

Cited By ~ 8

Author(s):

Akihiro Ohmoto ◽

Shinichi Yachida ◽

Chigusa Morizane

Keyword(s):

Pancreatic Cancer ◽

Checkpoint Inhibitors ◽

Susceptibility Gene ◽

Treatment Strategies ◽

Familial Pancreatic Cancer ◽

Cancer Syndrome ◽

Increased Risk ◽

Clinical Benefits ◽

Surveillance Programs ◽

Cancer Syndromes

Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM, which participate in homologous recombination repair, and further investigations are in progress. Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway.

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Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16061055 ◽

2019 ◽

Vol 16 (6) ◽

pp. 1055 ◽

Cited By ~ 3

Author(s):

Jiande Wu ◽

Tarun Mamidi ◽

Lu Zhang ◽

Chindo Hicks

Keyword(s):

Breast Cancer ◽

Somatic Mutation ◽

Triple Negative Breast Cancer ◽

Somatic Mutations ◽

Triple Negative ◽

Germline Mutations ◽

Biological Pathways ◽

Molecular Networks ◽

Increased Risk ◽

Mutation Information

Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of BRCA1 in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.

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The Contributions of Improved Therapy and Earlier Detection to Cancer Survival Gains, 1988-2000

Forum for Health Economics & Policy ◽

10.2202/1558-9544.1195 ◽

2010 ◽

Vol 13 (2) ◽

Cited By ~ 8

Author(s):

Eric Sun ◽

Anupam B Jena ◽

Darius Lakdawalla ◽

Carolina Reyes ◽

Tomas J Philipson ◽

...

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Lung Cancer ◽

Pancreatic Cancer ◽

Early Detection ◽

Cancer Survival ◽

Policy Implications ◽

Sensitivity Analyses ◽

Lower Percentage ◽

Conditional Survival

Prior literature has documented improvements in cancer survival over time. However, ambiguity remains over the relative contributions of improved treatment and earlier detection to survival gains. Using registry data, we developed a novel framework to estimate the relative contributions of advances in treatment and detection. Our approach compares changes in the probability of early detection, which we interpret as the effects of advances in detection, to improvements in stage-conditional survival, which we interpret as the effects of treatment. We applied this methodology using SEER data to estimate probabilities of early detection and stage-conditional survival curves for several cancers, by race, between 1988 and 2000. Survival increased for all of the cancers we examined, with blacks experiencing larger survival gains than whites for all cancers combined. Our baseline analysis found that treatment advances account for the vast majority of survival gains for all the cancers examined: breast cancer (83%), lung cancer (85%), colorectal cancer (76%), pancreatic cancer (100%), and non-Hodgkins lymphoma (96%). Compared to whites, treatments appear to explain a lower percentage of survival gains for blacks for all cancers combined; breast cancer, NHL, and pancreatic cancer show a higher percentage of survival gains than lung cancer; and roughly the same percentage for the colorectal cancer. These results are robust to sensitivity analyses examining potential length and lead time bias. Overall, our results suggest that while improved treatment and early detection both contributed to the recent gains in survival, the majority of gains from 1988 to 2000 appear to have been driven by better treatment, manifested by improved stage-conditional survival. These results have important policy implications regarding investment in research and development and the evaluation of efforts to improve cancer screening.

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