Identification of germline genetic mutations in patients with pancreatic cancer
Erin E. Salo-Mullen,Eileen M. O'Reilly,David P. Kelsen,Asad Ashraf,Maeve A. Lowery,Kenneth H. Yu,Diane Lauren Reidy,Andrew S. Epstein,Anne Lincoln,Amethyst Saldia,Lauren Jacobs,Rohini Rau-Murthy,Liying Zhang,Robert C. Kurtz,Leonard B. Saltz,Kenneth Offit,Mark E. Robson,Zsofia K. Stadler +17 more
Reads0
Chats0
TLDR
The authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC.Abstract:
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. Cancer 2015;121:4382–8. © 2015 American Cancer Society.read more
Citations
More filters
Journal ArticleDOI
Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic, version 2.2021
Mary B. Daly,Tuya Pal,Michael Berry,Saundra S. Buys,Patricia I. Dickson,Susan M. Domchek,Ahmed Elkhanany,Susan Hatters Friedman,Michael Goggins,Mollie L. Hutton,Beth Y. Karlan,Seema A. Khan,Catherine Klein,Wendy Kohlmann,Allison W. Kurian,Christine Laronga,Jennifer K. Litton,Julie S. Mak,Carolyn S. Menendez,Sofia D. Merajver,Barbara S. Norquist,Kenneth Offit,Holly J. Pederson,Gwen Reiser,Leigha Senter-Jamieson,Kristen M. Shannon,Rebecca Shatsky,Kala Visvanathan,Jeffrey N. Weitzel,Myra J. Wick,Kari B. Wisinski,Matthew B. Yurgelun,Susan Darlow,Mary A. Dwyer +33 more
TL;DR: The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies as mentioned in this paper.
Journal ArticleDOI
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020.
Mary B. Daly,Robert Pilarski,Matthew B. Yurgelun,Michael Berry,Saundra S. Buys,Patricia I. Dickson,Susan M. Domchek,Ahmed Elkhanany,Susan Hatters Friedman,Judy Garber,Michael Goggins,Mollie L. Hutton,Seema A. Khan,Catherine Klein,Wendy Kohlmann,Allison W. Kurian,Christine Laronga,Jennifer K. Litton,Julie S. Mak,Carolyn S. Menendez,Sofia D. Merajver,Barbara S. Norquist,Kenneth Offit,Tuya Pal,Holly J. Pederson,Gwen Reiser,Kristen M. Shannon,Kala Visvanathan,Jeffrey N. Weitzel,Myra J. Wick,Kari B. Wisinski,Mary A. Dwyer,Susan Darlow +32 more
TL;DR: These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genesassociated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.
Journal ArticleDOI
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma.
Koji Shindo,Jun Yu,Masaya Suenaga,Shahriar Fesharakizadeh,Christy Cho,Anne Macgregor-Das,Abdulrehman Siddiqui,P. Dane Witmer,Koji Tamura,Tae Jun Song,Jose Alejandro Almario,Aaron Brant,Michael Borges,Madeline Ford,Thomas Barkley,Jin He,Matthew J. Weiss,Christopher L. Wolfgang,Nicholas J. Roberts,Ralph H. Hruban,Alison P. Klein,Michael Goggins +21 more
TL;DR: Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with Pancreatic cancer without a significant family history of cancer, and will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.
Journal ArticleDOI
Implications of Genetic and Epigenetic Alterations of CDKN2A (p16INK4a) in Cancer
TL;DR: The genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers is highlighted and the restoration of genetic and epigenetic reactivation of CD KN2A is a practical approach for the prevention and therapy of cancer.
Journal ArticleDOI
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.
Maeve A. Lowery,Winston Wong,Emmet Jordan,Jonathan W. Lee,Yelena Kemel,Joseph Vijai,Diana Mandelker,Ahmet Zehir,Marinela Capanu,Erin E. Salo-Mullen,Angela G. Arnold,Kenneth H. Yu,Anna M. Varghese,David P. Kelsen,Robin Brenner,Erica S. Kaufmann,Vignesh Ravichandran,Semanti Mukherjee,Michael F. Berger,David M. Hyman,David S. Klimstra,Ghassan K. Abou-Alfa,Catherine Tjan,Christina M. Covington,Hannah Maynard,Peter J. Allen,Gokce Askan,Steven D. Leach,Christine A. Iacobuzio-Donahue,Mark E. Robson,Kenneth Offit,Zsofia K. Stadler,Eileen M. O'Reilly +32 more
TL;DR: Data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes, and suggest these PGAs are therapeutically actionable in about 5% to 10% of patients.
References
More filters
Journal ArticleDOI
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
Journal ArticleDOI
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Peter C.C. Fong,D. S. Boss,Timothy A. Yap,Andrew Tutt,Peijun Wu,Marja Mergui-Roelvink,Peter S. Mortimer,Helen Swaisland,Alan Lau,Mark J. O'Connor,Alan Ashworth,James Carmichael,Stan B. Kaye,Jan H.M. Schellens,Jan H.M. Schellens,Johann S. de Bono +15 more
TL;DR: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCa2 mutation.
Journal ArticleDOI
PD-1 blockade in tumors with mismatch repair deficiency.
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Nilofer S. Azad,Daniel A. Laheru,Ross C. Donehower,Brandon Luber,Todd S. Crocenzi,George A. Fisher,Steve M Duffy,James J. Lee,Minori Koshiji,James R. Eshleman,Robert A. Anders,Bert Vogelstein,Luis A. Diaz +19 more
TL;DR: MM status predicts clinical benefit of immune checkpoint blockade with pembrolizumab, and high total somatic mutation loads were associated with PFS.
Journal Article
Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.
TL;DR: Data from families with evidence of linkage to BRCA1 is used to estimate the age-specific risks of breast and ovarian cancer in BRCa1-mutation carriers and to examine the variation in risk between and within families.
Journal ArticleDOI
Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.
David C. Whitcomb,Michael C. Gorry,Preston Ra,William Furey,Michael Sossenheimer,Charles D. Ulrich,Stephen P. Martin,Lawrence K. Gates,Stephen T. Amann,Phillip P. Toskes,Roger A. Liddle,Kevin McGrath,Generoso Uomo,James Christopher Post,James Christopher Post,Garth D. Ehrlich +15 more
TL;DR: X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site, and that loss of this cleavage site would permit autodigestion resulting in pancreatitis.
Related Papers (5)
Whole genomes redefine the mutational landscape of pancreatic cancer.
Nicola Waddell,Marina Pajic,Ann-Marie Patch,David K. Chang,Karin S. Kassahn,Peter Bailey,Amber L. Johns,David Miller,Katia Nones,Kelly Quek,Michael C.J. Quinn,Alan J. Robertson,Muhammad Zaki Hidayatullah Fadlullah,Timothy J. C. Bruxner,Angelika N. Christ,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Craig Nourse,Ehsan Nourbakhsh,Shivangi Wani,Peter J. Wilson,Emma Markham,Nicole Cloonan,Matthew J. Anderson,J. Lynn Fink,Oliver Holmes,Stephen H. Kazakoff,Conrad Leonard,Felicity Newell,Barsha Poudel,Sarah Song,Darrin Taylor,Nick Waddell,Scott Wood,Qinying Xu,Jianmin Wu,Mark Pinese,Mark J. Cowley,Hong C. Lee,Marc D. Jones,Adnan Nagrial,Jeremy L. Humphris,Lorraine A. Chantrill,Venessa T. Chin,Angela Steinmann,Amanda Mawson,Emily S. Humphrey,Emily K. Colvin,Angela Chou,Christopher J. Scarlett,Andreia V. Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S. Samra,James G. Kench,Jessica A. Pettitt,Neil D. Merrett,Christopher W. Toon,Krishna Epari,Nam Q. Nguyen,Andrew Barbour,Nikolajs Zeps,Nigel B. Jamieson,Janet Graham,Simone P. Niclou,Rolf Bjerkvig,Robert Grützmann,Daniela Aust,Ralph H. Hruban,Anirban Maitra,Christine A. Iacobuzio-Donahue,Christopher L. Wolfgang,Richard A. Morgan,Rita T. Lawlor,Vincenzo Corbo,Claudio Bassi,Massimo Falconi,Giuseppe Zamboni,Giampaolo Tortora,Margaret A. Tempero,Anthony J. Gill,James R. Eshleman,Christian Pilarsky,Aldo Scarpa,Elizabeth A. Musgrove,John V. Pearson,Andrew V. Biankin,Sean M. Grimmond +88 more
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Thierry Conroy,Françoise Desseigne,Marc Ychou,Olivier Bouché,Rosine Guimbaud,Yves Becouarn,Antoine Adenis,Jean-Luc Raoul,Sophie Gourgou-Bourgade,Jaafar Bennouna,Jean-Baptiste Bachet,Faiza Khemissa-Akouz,Denis Péré-Vergé,Catherine Delbaldo,Eric Assenat,Bruno Chauffert,C. Montoto-Grillot,Michel Ducreux +17 more
Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation
Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
Talia Golan,Pascal Hammel,Michele Reni,Eric Van Cutsem,Teresa Macarulla,Michael J. Hall,Joon Oh Park,Daniel Hochhauser,Dirk Arnold,Do Youn Oh,Anke Reinacher-Schick,Giampaolo Tortora,Giampaolo Tortora,Hana Algül,Eileen M. O'Reilly,David McGuinness,Karen Y. Cui,Katia Schlienger,Gershon Y. Locker,Hedy L. Kindler +19 more