title: Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations.
abstract: BACKGROUND
  Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance.
  
  
  METHODS
  We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals).
  
  
  RESULTS
  T790M germline mutations occurred in approximately 1% of non-small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06).
  
  
  CONCLUSIONS
  Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.
authors.affiliation: *Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX; †Department of Pathology, UT Southwestern Medical Center, Dallas, TX; ‡Cancer Genetics, Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX; §Department of Clinical Science and McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX; ‖Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; ¶Department of Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; #Department of Radiology, UT Southwestern Medical Center, Dallas, TX; **Department of Clinical Science and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX; ††Department of Cardiovascular and Thoracic Surgery, UT Southwestern Medical Center, Dallas, TX; and ‡‡Department of Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX.
authors.forename: Adi
authors.initials: A
authors.lastname: Gazdar
authors.forename: Linda
authors.initials: L
authors.lastname: Robinson
authors.forename: Dwight
authors.initials: D
authors.lastname: Oliver
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Lori
authors.initials: L
authors.lastname: Watumull
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Kemp
authors.initials: K
authors.lastname: Kernstine
authors.forename: Joan H
authors.initials: JH
authors.lastname: Schiller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010375:Pedigree; D011379:Prognosis; D012907:Smoking / Q000235:genetics*; D013577:Syndrome; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors
references.citation: J Thorac Oncol. 2012 Jun;7(6):1049-52
references.pmid: 22588155
references.citation: Adv Exp Med Biol. 2010;685:220-7
references.pmid: 20687510
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):43-8
references.pmid: 16397022
references.citation: J Clin Oncol. 2002 Mar 15;20(6):1480-90
references.pmid: 11896095
references.citation: J Thorac Oncol. 2009 Jan;4(1):139-41
references.pmid: 19096324
references.citation: Endocr Pathol. 2004 Fall;15(3):227-31
references.pmid: 15640548
references.citation: J Natl Cancer Inst. 2009 Apr 15;101(8):541-3
references.pmid: 19351914
references.citation: Am J Surg Pathol. 2006 May;30(5):606-13
references.pmid: 16699315
references.citation: Clin Cancer Res. 2010 Jan 15;16(2):755-63
references.pmid: 20068085
references.citation: PLoS One. 2009 Oct 14;4(10):e7464
references.pmid: 19826477
references.citation: PLoS One. 2009;4(2):e4576
references.pmid: 19238210
references.citation: J Clin Oncol. 2007 Feb 10;25(5):472-8
references.pmid: 17290054
references.citation: J Thorac Oncol. 2011 Feb;6(2):395-6
references.pmid: 21252721
references.citation: J Thorac Oncol. 2013 Mar;8(3):373-84
references.pmid: 23370315
references.citation: Clin Transl Oncol. 2010 Feb;12(2):75-80
references.pmid: 20156777
references.citation: Nature. 2012 Nov 1;491(7422):56-65
references.pmid: 23128226
references.citation: Cancer Res. 2007 May 15;67(10):4665-70
references.pmid: 17510392
references.citation: Clin Cancer Res. 2013 Apr 15;19(8):2240-7
references.pmid: 23470965
references.citation: Cancer Res. 2005 Aug 15;65(16):7276-82
references.pmid: 16105816
references.citation: Nat Genet. 2005 Dec;37(12):1315-6
references.pmid: 16258541
references.citation: Ann Hematol. 2013 Apr;92(4):459-69
references.pmid: 23262795
references.citation: J Clin Oncol. 2013 Mar 10;31(8):1070-80
references.pmid: 23401451
references.citation: BMC Cancer. 2011 Sep 24;11:406
references.pmid: 21943394
references.citation: J Thorac Oncol. 2009 Dec;4(12):1490-5
references.pmid: 19844187
references.citation: PLoS One. 2007 Aug 29;2(8):e810
references.pmid: 17726540
references.citation: Nat Rev Cancer. 2007 Mar;7(3):169-81
references.pmid: 17318210
references.citation: Fam Cancer. 2008;7(1):15-26
references.pmid: 17564815
references.citation: J Thorac Oncol. 2009 Jan;4(1):1-4
references.pmid: 19096299
references.citation: J Thorac Oncol. 2011 Feb;6(2):244-85
references.pmid: 21252716
references.citation: Cancer Res. 2007 Aug 1;67(15):7319-26
references.pmid: 17671201
references.citation: J Thorac Oncol. 2006 Mar;1(3):231-9
references.pmid: 17409862
references.citation: PLoS Med. 2005 Mar;2(3):e73
references.pmid: 15737014
references.citation: J Natl Cancer Inst. 2005 Mar 2;97(5):339-46
references.pmid: 15741570
references.citation: Adv Otorhinolaryngol. 2011;70:84-90
references.pmid: 21358189
references.citation: Nat Rev Clin Oncol. 2009 Jun;6(6):352-66
references.pmid: 19483740