Identification of germline genetic mutations in patients with pancreatic cancer Journal Article


Authors: Salo-Mullen, E. E.; O'Reilly, E. M.; Kelsen, D. P.; Ashraf, A. M.; Lowery, M. A.; Yu, K. H.; Reidy, D. L.; Epstein, A. S.; Lincoln, A.; Saldia, A.; Jacobs, L. M.; Rau-Murthy, R.; Zhang, L.; Kurtz, R. C.; Saltz, L.; Offit, K.; Robson, M. E.; Stadler, Z. K.
Article Title: Identification of germline genetic mutations in patients with pancreatic cancer
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.
Keywords: adult; controlled study; aged; major clinical study; genetics; pancreas cancer; germline; cancer susceptibility; prevalence; cohort analysis; genetic association; heterozygote; tumor suppressor gene; family history; genetic susceptibility; pancreatic cancer; genetic screening; brca; protein mlh1; lynch syndrome; mlh1 gene; hereditary; p16; hereditary nonpolyposis colorectal cancer; genetic identification; mutations; palb2; germline mutation; ashkenazi jewish; ashkenazi jew; human; male; female; priority journal; article
Journal Title: Cancer
Volume: 121
Issue: 24
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2015-12-15
Start Page: 4382
End Page: 4388
Language: English
DOI: 10.1002/cncr.29664
PROVIDER: scopus
PUBMED: 26440929
PMCID: PMC5193099
DOI/URL:
Notes: Article -- Export Date: 7 January 2016 -- 4382 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    507 Offit
  2. Leonard B Saltz
    580 Saltz
  3. Mark E Robson
    365 Robson
  4. Liying Zhang
    88 Zhang
  5. Zsofia Kinga Stadler
    144 Stadler
  6. Diane Lauren Reidy
    146 Reidy
  7. Maeve Aine Lowery
    96 Lowery
  8. Kenneth Ho-Ming Yu
    58 Yu
  9. Andrew Saul Epstein
    68 Epstein
  10. Eileen O'Reilly
    316 O'Reilly
  11. Robert C Kurtz
    132 Kurtz
  12. David P Kelsen
    332 Kelsen
  13. Lauren Michelle Jacobs
    10 Jacobs
  14. Anne Gunning Lincoln
    14 Lincoln
  15. Asad   Ashraf
    6 Ashraf
  16. Catherine Amethyst Saldia
    5 Saldia