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Germline mutations predisposing to non-small cell lung cancer

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Abstract

Lung cancer in multiple first degree relatives had previously been attributed to smoking and to inherited enzymes associated with increased activation of carcinogens in smoke. There was not clear agreement on the significance of the testing methods for lung cancer susceptibility. More recent studies have identified germline mutations associated with lung cancer even in the absence of smoking and other mutations with plausible explanations for their association with lung cancer caused by smoking. At this time, the clinical significance of the various germline mutations for screening and the implications for therapy are not certain. This review summarizes the currently identified germline mutations associated with lung cancer, but this growing area of research will very likely identify further significant mutations as well.

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References

  1. Thomas A, Xi L, Carter CA et al (2013) Concurrent molecular alterations in tumors with germ line epidermal growth factor receptor T790M mutations. Clin Lung Cancer 14(4):452–456

    Article  CAS  PubMed  Google Scholar 

  2. Wang Y, McKay JD, Rafnar T et al (2014) Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat Genet 46(7):736–741

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Helgadottir H, Hoiom V, Jonsson G et al (2014) High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families. J Med Genet 51(8):545–552

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Abdel-Rahman MH, Pilarski R, Cebulla CM et al (2011) Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 48(12):856–859

    Article  CAS  PubMed  Google Scholar 

  5. Goel N, Ortel TL, Bali D et al (1999) Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance. Arthritis Rheum 42(2):318–327

    Article  CAS  PubMed  Google Scholar 

  6. Tokuhata GK, Lilienfeld AM (1963) Familial aggregation of lung cancer in humans. J Natl Cancer Inst 30:289–312

    CAS  PubMed  Google Scholar 

  7. Amos CI, Wu X, Broderick P et al (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40(5):616–622

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Amos CI, Pinney SM, Li Y et al (2010) A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers. Cancer Res 70(6):2359–2367

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Oxnard GR, Miller VA, Robson ME et al (2012) Screening for germline EGFR T790M mutations through lung cancer genotyping. J Thorac Oncol 7(6):1049–1052

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Vikis H, Sato M, James M et al (2007) EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Cancer Res 67(10):4665–4670

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Girard N, Lou E, Azzoli CG et al (2010) Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Clin Cancer Res 16(2):755–763

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. van Noesel J, van der Ven WH, van Os TA et al (2013) Activating germline R776H mutation in the epidermal growth factor receptor associated with lung cancer with squamous differentiation. J Clin Oncol 31(10):e161–e164

    Article  PubMed  Google Scholar 

  13. Centeno I, Blay P, Santamaria I et al (2011) Germ-line mutations in epidermal growth factor receptor (EGFR) are rare but may contribute to oncogenesis: a novel germ-line mutation in EGFR detected in a patient with lung adenocarcinoma. BMC Cancer 11:172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Ohtsuka K, Ohnishi H, Kurai D et al (2011) Familial lung adenocarcinoma caused by the EGFR V843I germ-line mutation. J Clin Oncol 29(8):e191–e192

    Article  PubMed  Google Scholar 

  15. Matsushima S, Ohtsuka K, Ohnishi H et al (2014) V843I, a lung cancer predisposing EGFR mutation, is responsible for resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 9(9):1377–1384

    Article  CAS  PubMed  Google Scholar 

  16. Demierre N, Zoete V, Michielin O et al (2013) A dramatic lung cancer course in a patient with a rare EGFR germline mutation exon 21 V843I: is EGFR TKI resistance predictable? Lung Cancer 80(1):81–84

    Article  PubMed  Google Scholar 

  17. Ikeda K, Nomori H, Mori T, Sasaki J, Kobayashi T (2008) Novel germline mutation: EGFR V843I in patient with multiple lung adenocarcinomas and family members with lung cancer. Ann Thorac Surg 85(4):1430–1432

    Article  PubMed  Google Scholar 

  18. Prim N, Legrain M, Guerin E et al (2014) Germ-line exon 21 EGFR mutations, V843I and P848L, in nonsmall cell lung cancer patients. Eur Respir Rev 23(133):390–392

    Article  PubMed  Google Scholar 

  19. Yamamoto H, Higasa K, Sakaguchi M et al (2014) Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J Natl Cancer Inst 106(1):djt338

    Article  PubMed Central  PubMed  Google Scholar 

  20. Gachechiladze M, Skarda J (2012) The role of BRCA1 in non-small cell lung cancer. Biomed Pap 156(3):200–203

    Article  CAS  Google Scholar 

  21. Potrony M, Puig-Butille JA, Aguilera P et al (2014) Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling. J Am Acad Dermatol 71(5):888–895

  22. Nolan L, Eccles D, Cross E et al (2009) First case report of Muir–Torre syndrome associated with non-small cell lung cancer. Fam Cancer 8(4):359–362

    Article  CAS  PubMed  Google Scholar 

  23. Canney A, Sheahan K, Keegan D, Tolan M, Hyland J, Green A (2009) Synchronous lung tumours in a patient with metachronous colorectal carcinoma and a germline MSH2 mutation. J Clin Pathol 62(5):471–473

    Article  CAS  PubMed  Google Scholar 

  24. van Lier MG, Wagner A, Mathus-Vliegen EM, Kuipers EJ, Steyerberg EW, van Leerdam ME (2010) High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105(6):1258–1264 author reply 1265

    Article  PubMed  Google Scholar 

  25. Fernandez P, Carretero J, Medina PP et al (2004) Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations. Oncogene 23(29):5084–5091

    Article  CAS  PubMed  Google Scholar 

  26. Marees T, Moll AC, Imhof SM, de Boer MR, Ringens PJ, van Leeuwen FE (2008) Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst 100(24):1771–1779

    Article  PubMed  Google Scholar 

  27. Wang Y, Kuan PJ, Xing C et al (2009) Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet 84(1):52–59

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Brennan P, Hainaut P, Boffetta P (2011) Genetics of lung-cancer susceptibility. Lancet Oncol 12(4):399–408

    Article  CAS  PubMed  Google Scholar 

  29. Wu H, Zhu R (2014) Quantitative assessment of common genetic variants on chromosome 5p15 and lung cancer risk. Tumour Biol 35(6):6055–6063

    Article  CAS  PubMed  Google Scholar 

  30. Hung RJ, McKay JD, Gaborieau V et al (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452(7187):633–637

    Article  CAS  PubMed  Google Scholar 

  31. Hansen HM, Xiao Y, Rice T et al (2010) Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans. Hum Mol Genet 19(18):3652–3661

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Schwartz AG, Cote ML, Wenzlaff AS, Land S, Amos CI (2009) Racial differences in the association between SNPs on 15q25.1, smoking behavior, and risk of non-small cell lung cancer. J Thorac Oncol 4(10):1195–1201

    Article  PubMed Central  PubMed  Google Scholar 

  33. Renieri A, Mencarelli MA, Cetta F et al (2014) Oligogenic germline mutations identified in early non-smokers lung adenocarcinoma patients. Lung Cancer 85(2):168–174

    Article  PubMed  Google Scholar 

  34. Dai X, Deng S, Wang T et al (2014) Associations between 25 lung cancer risk-related SNPs and polycyclic aromatic hydrocarbon-induced genetic damage in coke oven workers. Cancer Epidemiol Biomark Prev 23(6):986–996

    Article  CAS  Google Scholar 

  35. Tseng TS, Park JY, Zabaleta J et al (2014) Role of nicotine dependence on the relationship between variants in the nicotinic receptor genes and risk of lung adenocarcinoma. PLoS One 9(9):e107268

    Article  PubMed Central  PubMed  Google Scholar 

  36. Schwartz AG, Ruckdeschel JC (2006) Familial lung cancer: genetic susceptibility and relationship to chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173(1):16–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Schwartz AG (2012) Genetic epidemiology of cigarette smoke-induced lung disease. Proc Am Thorac Soc 9(2):22–26

    Article  PubMed Central  PubMed  Google Scholar 

  38. Bailey-Wilson JE, Amos CI, Pinney SM et al (2004) A major lung cancer susceptibility locus maps to chromosome 6q23–25. Am J Hum Genet 75(3):460–474

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Brenner DR, Boffetta P, Duell EJ et al (2012) Previous lung diseases and lung cancer risk: a pooled analysis from the International Lung Cancer Consortium. Am J Epidemiol 176(7):573–585

    Article  PubMed Central  PubMed  Google Scholar 

  40. Yang JC, Kim D, Planchard D et al (2014) Updated safety and efficacy from a phase I study of AZD9291 in patients with EGFR-TKI reistant non-small cell lung cancer. Ann Oncol 25(supplement 4), abstract 449PD

  41. Paigen B, Gurtoo HL, Minowada J et al (1977) Questionable relation of aryl hydrocarbon hydroxylase to lung-cancer risk. N Engl J Med 297(7):346–350

    Article  CAS  PubMed  Google Scholar 

  42. Shaw GL, Weiffenbach B, Falk RT et al (1997) Frequency of the variant allele CYP2D6(C) among North American Caucasian lung cancer patients and controls. Lung Cancer 17(1):61–68

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Gerald H. Clamon.

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Clamon, G.H., Bossler, A.D., Hejleh, T.A. et al. Germline mutations predisposing to non-small cell lung cancer. Familial Cancer 14, 463–469 (2015). https://doi.org/10.1007/s10689-015-9796-x

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