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Table 2 Lung cancers with germline cancer predisposing genes detected and somatic EGFR mutation information in lung cancer-clustering families

From: Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

Germline genes or lociGermline mutationsCase #Family #RelationSexAgeEthnicitySmokingHistologySomatic EGFR mutationCommentRef.
EGFRp.T790 M11ProbandM50WhiteS5 × ADCs2 × L858R, 1 × 19del, 2 × WTMother (F, 62, BAC); Maternal grandfather (M, 72, BAC); Maternal great uncle (M, 60s, BAC); Brother (51, male, multi-nodules) and Sister (48, female, unaffected) carried germline EGFR p.T790 MBell, et al. 2005 [36]
  21BrotherM55WhiteSADCG719A  
EGFRp.T790 M32ProbandF72NRNS1 × ADC + 1× BAC + 1 × LCC3 × WTSister affected with lung cancerPrudkin, et al. 2009 [37]
EGFRp.T790 M43ProbandF62NRNSADCWTMother had lung cancerPrudkin, et al. 2009 [37]
EGFRp.T790 M54ProbandF72WhiteNSADC19delInconsistent records in the pedigree (aged 73 and having SCC)Tibaldi, et al. 2011 [38]
  64SisterF74WhiteNSNSCLCWTExon 20 was not examined due to insufficient tumour tissue.
EGFRp.T790 M75ProbandF70NRSADCWTFather (M, 60s, smoker, lung cancer); brother (male, 62, smoker, throat cancer); Proband had somatic K-RAS mutation.Thomas, et al. 2013 [39]
EGFRp.T790 M86ProbandF58NRSADCL858RMother (female, 70s, non-smoker, BAC); brother (male, 45, ADC), brother (male, 51, non-smoker, bilateral lung nodules of uncertain cause at follow-up)Thomas, et al. 2013 [39]
EGFRp.T790 M97ProbandF29WhiteLSADCL858RProband also had multiple lesions including AAH, AIS and MIA. Fourteen carriers with known, obligate or assumed mutations in the family pedigree; in these carriers, 4 had lung cancer. In Five unaffected mutation carriers, four had multiple nodules and the other one had single sub-cm solid nodule.Gazdar, et al. 2014 [40]
EGFRp.T790 M108ProbandF44NRNS7 × ADCs4 × L858R, 2 × 19del, 1 × WTThe EGFR wild-type ADC had somatic ARID1A p.K1938 N. Family history of breast and ovarian cancer in maternal relatives (2nd-degree); germline BRCA2 p.L459S variant of uncertain significance detected. Mother with metastatic ADC (germline T790 M carrier, unknown age, BRCA1/2 not detected); Daughter carried germline T790 M.Yu, et al. 2014 [41]
EGFRp.T790 M119ProbandF34WhiteNSADCL858RFamily history of lung and other cancers (paternal relatives); no germline EGFR T790 M status available in other membersLou, et al. 2016 [42]
EGFRp.R776H1210ProbandF57WhiteNSNSCLCG719ANSCLC with squamous component inside. Only a brother detected and did not carry the germline R776H mutation.Van Noesel, et al. 2013 [43]
  1310DaughterF36WhiteNSSCCG719S 
EGFRp.V769 M1411ProbandM57JewishS5 × ADCs2 × G719A, 2 × (G719C + S768I), 1 × G719SFamily history of other cancers (breast and ovarian cancers in the 2nd-degree maternal relatives), did not examine BRCA1/2; the proband also present several small lung nodules in the lung postoperativelyHellman, et al. 2017 [44]
EGFRp.V843I1512ProbandF70AsianUK3 ADCs + 4 BACs + 3 AAHs3 × L858R (1 ADC, 1 BAC, 1 AAH), 2 × L861Q (2 ADCs)Other 5 lesions haven’t been examined. Father and a brother died of lung cancer. A healthy sister and another unaffected brother carried the germline V831I mutation.Ikeda, et al. 2008 [45]
EGFRp.V843I1613ProbandF78AsianUKADCL858RAunt had ADC at 70 (germline not examined). A nephew had non-Hodgkin’s lymphoma at 12 (germline V843I negative). A healthy daughter carried germline V843I mutation.Ohtsuka, et al. 2011 [46]
  1713MotherF70AsianUKADCL858R
  1813BrotherM41AsianUKADCL858R
EGFRp.V834 L1914ProbandF57SurinamSADCL858RA daughter carried germline V834 L; Father died of massive hemoptysis of unknown cause.Van der Leest, et al. 2018 [47]
  2014BrotherM57SurinamSNSCLCL858R
  2114SisterF46SurinamNSNSCLCL858R
  2214DaughterF42SurinamNSNSCLCL858R
HER2p.G660D2315ProbandF44AsianLSMulti-ADCsWTHER2 Family history of lung cancers among multiple maternal members; Daughter with germline G660D, and CT showed multiple GGNs in bilateral lungs at 30 (light smoker).Yamamoto, et al. 2014 [48]
  2415MotherF74AsianNSMulti-ADCsWT 
METp.N375K2516ProbandF75AsianNSADCL858RAnother sister (never-smoker) clinically diagnosed with lung cancer at 80.Tode, et al. 2017 [49]
  2616SisterF63AsianNSADC19del
  2716SisterF63AsianLSADCL858R
CHEK2p.R474C (homozygous)2817ProbandM60AsianNSMulti-ADCs,NRProband: colon and prostate cancer affected. Father (60 year): prostate and gastric cancer; Mother (79 year): solitary lung cancer; A son (1 year 10 moths): neuroblastoma.Kukita, et al. 2016 [50]
  2917SisterF60AsianNS7 ADCs,L858R or 19delUterine myoma and breast cancer affected 
BRCA2c.9641insT3018ProbandM43WhiteNSADCExon 20insFamily history of breast cancer in maternal relatives and lung cancer in maternal grandfather (never smoker)Marks, et al. 2008 [51]
BRCA2c.8867del53119ProbandM74WhiteLSADC19delFamily history of breast or ovarian cancers in daughter, mother and maternal aunt. Daughter carried germline BRCA2 c.8867del5 mutation.Marks, et al. 2008 [51]
TP53p.R273H3220ProbandF34NRNSADC19delProband: breast cancer affected at 30 (somatic HER2+, EGFR-). Mother with bilateral breast cancer at 35; Sister 1 with breast liposarcoma at 26 (germline TP53 p.R273H); Sister 2 with breast cancer at 33 (germline TP53 p.R273H); maternal grandmother with breast cancer at early 40s; Brother unaffected (germline TP53 p.R273H); Sister 3 without germline TP53 mutation; all without germline BRCA1/2.Bemis, et al. 2007 [52]
TP53p.G245S3321ProbandF43HispanicNSADCL858RConcurrent somatic HER2 p.S310F. Germline BRCA1/2 negative. Affected breast cancer at 44, gluteal schwannoma at 46 and atypical leiomyoma. Sister and Aunt with breast cancer at 40s; Cousin with brain tumour at a young age; Mother with leukaemia.Jia, et al. 2014 [53]
TP53exon 19 deletion3422ProbandF51WhiteNSADCL858RProband: bilateral breast cancers and malignant fibrous histiocytoma affected. Mother, maternal aunts, two first cousins and maternal grandmother died of early-onset cancers (< 60 years)Michalarea, et al. 2014 [54]
TP53p.H179Y3523ProbandM55NRNSADC19delT790 M mutation (post-TKI) detected; No somatic alterations on HER2, PI3KCA, BRAF, KRAS or ALK genes. Descendants affected with unusual childhood tumours.Ricordel, et al. 2015 [55]
TP53p.R273H3624ProbandF57NRNSADCL858RAffected with breast cancer as well. No somatic alterations on HER2, PI3KCA, BRAF, KRAS or ALK genes. Daughter affected with corticosurrenaloma.Ricordel, et al. 2015 [55]
TP53p.G245S3725ProbandF30NRNRADC19 delDaughter affected with sarcoma at 10. Another two children are carriers.Pathak, et al. 2018 [56]
TP53/CDH1p.R196a; CDH1 p.N570=3826ProbandF26HispanicNS3 ADC1 × 19delProband: the other two ADCs with EGFR amplification and PIK3CA p.E545K. Intra-alveolar lung tumour spread with K-RAS p.G12C + BRAF p.L597 V; Osteosarcoma affected at 12 (somatic PIK3CA p.E545K + K-RAS p.G12S + CDH1 p.A617T). Mother with breast cancer at 32; Maternal Uncle with facial and orbitary chondrosarcoma at 14 and diffuse gastric cancer at 24; Maternal Uncle with anaplastic astrocytoma at 13; Maternal Cousin with diffuse gastric cancer at 36 (germline CDH1 p.Leu721Val); Maternal Cousin with EGFR-mutated lung cancer at 26; Maternal Grandmother with breast cancer at 50, melanoma at 44 and colon cancer at 50; Paternal Aunt with breast cancer at 48.Cardona, et al. 2018 [57]
TP53p.R248W3927Proband aF34NRNS2 ADC1 × exon 20insThe other ADC had HER2 (amplification + p.V659E). Affected bilateral breast ductal carcinoma in situ at 29. Did not report family history.Serra, et al. 2013 [58]
TP53/PMS2p.V157D/ p.R20Q4028ProbandM22AsianNRADC19delFamily history of a wide variety of tumours (including breast cancer, lung cancer) among family members (affected <=54, half of them < 31 years); father (31, died of colon cancer, K-RAS p.G12D mutation in colon tumour) carried the two germline mutationsWang, et al. 2014 [59]
APCc.TCA1110TGA4129ProbandF43AsianNSADCWTNo germline MYH mutations; Somatic K-RAS and p53 wild-type; amplification of three regions 5p, 8q, and 12q14-12q2; affected with FAP at 26, duodenal adenomas at 33. Father with FAP; Son with FAP and medulloblastoma; Paternal great aunt with FAP (whose son was affected with FAP and desmoid tumour, granddaughter with FAP, gastric and thyroid cancer).Shinmura, et al. 2008 [60]
  1. Abbreviations: AAH atypical adenomatous hyperplasia, ADC adenocarcinoma, AIS adenocarcinoma in situ, BAC bronchioloalveolar carcinoma, F female, FAP familial adenomatous polyposis, GGN ground-glass nodule, LS light smoker, M male, MIA minimally invasive adenocarcinoma, NS never smoker, NSCLC non-small cell lung cancer, S smoker, SCC squamous cell lung cancer, WT wild type. Genes were noted as italics
  2. aThe original publication did not report family history of cancer of the index case, but we included it here due to its diagnosis of familial Li-Fraumeni Syndrome