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Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Pancreatic cancer (PC) is categorized as a neoplasm associated with Lynch syndrome; however, the precise proportion of PC patients harboring DNA mismatch repair genes (MMR genes) remains unclear, especially in the Asian population.

Methods

Among 304 Japanese patients with pathologically proven pancreatic ductal adenocarcinoma, we selected 20 (6.6%) patients with a personal or family history involving first- or second-degree relatives fulfilling the revised Bethesda guidelines (RBG), defined as RBG-compatible cases. We analyzed germline variants in 21 genes related to a hereditary predisposition for cancer as well as clinical features in all 20 cases.

Results

The RBG-compatible cases did not show any unique clinicopathological features. Targeted sequencing data revealed three patients carrying deleterious or likely deleterious variants. Specifically, these three patients harbored a nonsense variant in ATM, a frameshift variant in ATM, and a concurrent nonsense variant in PMS2 and missense variant in CHEK2 (double-mutation carrier), respectively. Although an MMR gene mutation was identified in only one of the 20 patients, up to 15% of the RBG-compatible PC cases were associated with germline deleterious or likely deleterious variants.

Conclusions

These findings showed that these guidelines could be useful for identifying PC patients with DNA damage repair genes as well as MMR genes.

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References

  1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    Article  CAS  Google Scholar 

  2. Matsubayashi H. Familial pancreatic cancer and hereditary syndromes: screening strategy for high-risk individuals. J Gastroenterol. 2011;46:1249–59.

    Article  Google Scholar 

  3. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.

    Article  CAS  Google Scholar 

  4. Møller P, Seppälä TT, Bernstein I, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome database. Gut. 2017. https://doi.org/10.1136/gutjnl-2017-314057.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Smyrk TC, Watson P, Kaul K, et al. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001;91:2417–22.

    Article  CAS  Google Scholar 

  6. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  Google Scholar 

  7. Humphris JL, Patch AM, Nones K, et al. Hypermutation in pancreatic cancer. Gastroenterology. 2017;152:68–74.

    Article  CAS  Google Scholar 

  8. Laitman Y, Herskovitz L, Golan T, et al. The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer. Fam Cancer. 2012;11:243–7.

    Article  CAS  Google Scholar 

  9. Gargiulo S, Torrini M, Ollila S, et al. Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome. Fam Cancer. 2009;8:547–53.

    Article  CAS  Google Scholar 

  10. Grant RC, Selander I, Connor AA, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. 2015;148:556–64.

    Article  CAS  Google Scholar 

  11. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  CAS  Google Scholar 

  12. McKenna A, Hanna M, Banks E, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    Article  CAS  Google Scholar 

  13. 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–73.

    Article  Google Scholar 

  14. 1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.

    Article  Google Scholar 

  15. Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.

    Article  CAS  Google Scholar 

  16. Landrum MJ, Lee JM, Riley GR, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980–5.

    Article  CAS  Google Scholar 

  17. Thompson BA, Spurdle AB, Plazzer JP, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2014;46:107–15.

    Article  CAS  Google Scholar 

  18. Vallée MP, Francy TC, Judkins MK, et al. Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum Mutat. 2012;33:22–8.

    Article  Google Scholar 

  19. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81.

    Article  CAS  Google Scholar 

  20. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    Article  CAS  Google Scholar 

  21. Schwarz JM, Cooper DN, Schuelke M, et al. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.

    Article  CAS  Google Scholar 

  22. Shihab HA, Gough J, Cooper DN, et al. Predicting the functional, molecular and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum Mutat. 2013;34:57–65.

    Article  CAS  Google Scholar 

  23. Shihab HA, Gough J, Cooper DN, et al. Predicting the functional consequences of cancer-associated amino acid substitutions. Bioinformatics. 2013;29:1504–10.

    Article  CAS  Google Scholar 

  24. Shihab HA, Gough J, Mort M, et al. Ranking non-synonymous single nucleotide polymorphisms based on disease concepts. Hum Genom. 2014;8:11.

    Article  Google Scholar 

  25. Liu Y, Liao J, Xu Y, et al. A recurrent CHEK2 p.H371Y mutation is associated with breast cancer risk in Chinese women. Hum Mutat. 2011;32:1000–3.

    Article  CAS  Google Scholar 

  26. Baloch AH, Daud S, Raheem N, et al. Missense mutations (p. H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin. Mol Biol Rep. 2014;41:1103–7.

    Article  CAS  Google Scholar 

  27. Chen W, Yurong S, Liansheng N. Breast cancer low-penetrance allele 1100delC in the CHEK2 gene: not present in the Chinese familial breast cancer population. Adv Ther. 2008;25:496–501.

    Article  Google Scholar 

  28. de Miranda NF, Peng R, Georgiou K, et al. DNA repair genes are selectively mutated in diffuse large B cell lymphomas. J Exp Med. 2013;210:1729–42.

    Article  Google Scholar 

  29. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:5783–8.

    Article  Google Scholar 

  30. Julié C, Trésallet C, Brouquet A, et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol. 2008;103:2825–35.

    Article  Google Scholar 

  31. Rodríguez-Moranta F, Castells A, Andreu M, et al. Clinical performance of original and revised Bethesda guidelines for the identification of MSH2/MLH1 gene carriers in patients with newly diagnosed colorectal cancer: proposal of a new and simpler set of recommendations. Am J Gastroenterol. 2006;101:1104–11.

    Article  Google Scholar 

  32. Piñol V, Castells A, Andreu M, et al. Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005;293:1986–94.

    Article  Google Scholar 

  33. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–60.

    Article  CAS  Google Scholar 

  34. Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;35:1086–95.

    Article  CAS  Google Scholar 

  35. Pérez-Carboneli L, Ruiz-Ponte C, Guarinos C, et al. Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer. Gut. 2012;61:865–72.

    Article  Google Scholar 

  36. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Am J Gastroenterol. 2014;109:1159–79.

    Article  Google Scholar 

  37. Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62:812–23.

    Article  CAS  Google Scholar 

  38. Klein AP. Identifying people at a high risk of developing pancreatic cancer. Nat Rev Cancer. 2013;13:66–74.

    Article  CAS  Google Scholar 

  39. Takai E, Yachida S, Shimizu K, et al. Germline mutations in Japanese familial pancreatic cancer patients. Oncotarget. 2016;7:74227–35.

    PubMed  PubMed Central  Google Scholar 

  40. Renwick A, Thompson D, Seal S, et al. Breast Cancer Susceptibility Collaboration (UK). ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38:873–5.

    Article  CAS  Google Scholar 

  41. Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005;97:813–22.

    Article  CAS  Google Scholar 

  42. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6.

    Article  CAS  Google Scholar 

  43. Kim H, Saka B, Knight S, et al. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. Clin Cancer Res. 2014;20:1865–72.

    Article  CAS  Google Scholar 

  44. Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15:1781–91.

    Article  CAS  Google Scholar 

  45. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.

    Article  CAS  Google Scholar 

  46. Cybulski C, Wokołorczyk D, Jakubowska A, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol. 2011;29:3747–52.

    Article  CAS  Google Scholar 

  47. Lener MR, Kashyap A, Kluźniak W, et al. The prevalence of founder mutations among individuals from families with familial pancreatic cancer syndrome. Cancer Res Treat. 2017;49:430–6.

    Article  CAS  Google Scholar 

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Acknowledgements

We wish to thank all of the patients and their families who contributed to this study. We also thank Dr. Kokichi Sugano and Dr. Teruhiko Yoshida (Department of Genetic Medicine and Services, National Cancer Center Hospital).

Funding

This work was supported by the National Cancer Center Research and Development Fund (28-A-1 to S.Y. and C.M.), the Takeda Science Foundation (to S.Y.), and the Pancreas Research Foundation of Japan (to A.O.). The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan.

Author information

Authors and Affiliations

  1. Laboratory of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan

    Akihiro Ohmoto, Erina Takai & Shinichi Yachida

  2. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 1040045, Japan

    Chigusa Morizane, Emi Kubo, Hiroko Hosoi, Yasunari Sakamoto, Shunsuke Kondo, Hideki Ueno & Takuji Okusaka

  3. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan

    Kazuaki Shimada

  4. Department of Cancer Genome Informatics, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan

    Shinichi Yachida

Authors
  1. Akihiro Ohmoto
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  2. Chigusa Morizane
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Correspondence to Chigusa Morizane.

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Ohmoto, A., Morizane, C., Kubo, E. et al. Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines. J Gastroenterol 53, 1159–1167 (2018). https://doi.org/10.1007/s00535-018-1466-y

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  • DOI: https://doi.org/10.1007/s00535-018-1466-y

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