Advertisement

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

  • Akihiro Ohmoto
  • Chigusa Morizane
  • Emi Kubo
  • Erina Takai
  • Hiroko Hosoi
  • Yasunari Sakamoto
  • Shunsuke Kondo
  • Hideki Ueno
  • Kazuaki Shimada
  • Shinichi Yachida
  • Takuji Okusaka
Original Article—Liver, Pancreas, and Biliary Tract
  • 194 Downloads

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.

Keywords

Pancreatic cancer Lynch syndrome DNA mismatch repair genes Revised Bethesda guidelines Germline variants 

Notes

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.

Compliance with ethical standards

Conflict of interest

All the authors declare no potential conflicts of interest.

Supplementary material

535_2018_1466_MOESM1_ESM.xlsx (17 kb)
Supplementary material 1 (XLSX 16 kb)

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 2.
    Matsubayashi H. Familial pancreatic cancer and hereditary syndromes: screening strategy for high-risk individuals. J Gastroenterol. 2011;46:1249–59.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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.Google Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Humphris JL, Patch AM, Nones K, et al. Hypermutation in pancreatic cancer. Gastroenterology. 2017;152:68–74.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 11.
    Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 15.
    Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 20.
    Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Schwarz JM, Cooper DN, Schuelke M, et al. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 23.
    Shihab HA, Gough J, Cooper DN, et al. Predicting the functional consequences of cancer-associated amino acid substitutions. Bioinformatics. 2013;29:1504–10.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Shihab HA, Gough J, Mort M, et al. Ranking non-synonymous single nucleotide polymorphisms based on disease concepts. Hum Genom. 2014;8:11.CrossRefGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Klein AP. Identifying people at a high risk of developing pancreatic cancer. Nat Rev Cancer. 2013;13:66–74.CrossRefPubMedGoogle Scholar
  39. 39.
    Takai E, Yachida S, Shimizu K, et al. Germline mutations in Japanese familial pancreatic cancer patients. Oncotarget. 2016;7:74227–35.PubMedPubMedCentralGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 42.
    Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15:1781–91.CrossRefPubMedGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Akihiro Ohmoto
    • 1
  • Chigusa Morizane
    • 2
  • Emi Kubo
    • 2
  • Erina Takai
    • 1
  • Hiroko Hosoi
    • 2
  • Yasunari Sakamoto
    • 2
  • Shunsuke Kondo
    • 2
  • Hideki Ueno
    • 2
  • Kazuaki Shimada
    • 3
  • Shinichi Yachida
    • 1
    • 4
  • Takuji Okusaka
    • 2
  1. 1.Laboratory of Clinical GenomicsNational Cancer Center Research InstituteTokyoJapan
  2. 2.Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center HospitalTokyoJapan
  3. 3.Department of Hepatobiliary and Pancreatic SurgeryNational Cancer Center HospitalTokyoJapan
  4. 4.Department of Cancer Genome Informatics, Graduate School of Medicine/Faculty of MedicineOsaka UniversityOsakaJapan

Personalised recommendations