Table 2.
Lung cancers with germline cancer predisposing genes detected and somatic EGFR mutation information in lung cancer-clustering families
| Germline genes or loci | Germline mutations | Case # | Family # | Relation | Sex | Age | Ethnicity | Smoking | Histology | Somatic EGFR mutation | Comment | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| EGFR | p.T790 M | 1 | 1 | Proband | M | 50 | White | S | 5 × ADCs | 2 × L858R, 1 × 19del, 2 × WT | Mother (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 M | Bell, et al. 2005 [36] |
| 2 | 1 | Brother | M | 55 | White | S | ADC | G719A | ||||
| EGFR | p.T790 M | 3 | 2 | Proband | F | 72 | NR | NS | 1 × ADC + 1× BAC + 1 × LCC | 3 × WT | Sister affected with lung cancer | Prudkin, et al. 2009 [37] |
| EGFR | p.T790 M | 4 | 3 | Proband | F | 62 | NR | NS | ADC | WT | Mother had lung cancer | Prudkin, et al. 2009 [37] |
| EGFR | p.T790 M | 5 | 4 | Proband | F | 72 | White | NS | ADC | 19del | Inconsistent records in the pedigree (aged 73 and having SCC) | Tibaldi, et al. 2011 [38] |
| 6 | 4 | Sister | F | 74 | White | NS | NSCLC | WT | Exon 20 was not examined due to insufficient tumour tissue. | |||
| EGFR | p.T790 M | 7 | 5 | Proband | F | 70 | NR | S | ADC | WT | Father (M, 60s, smoker, lung cancer); brother (male, 62, smoker, throat cancer); Proband had somatic K-RAS mutation. | Thomas, et al. 2013 [39] |
| EGFR | p.T790 M | 8 | 6 | Proband | F | 58 | NR | S | ADC | L858R | Mother (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] |
| EGFR | p.T790 M | 9 | 7 | Proband | F | 29 | White | LS | ADC | L858R | Proband 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] |
| EGFR | p.T790 M | 10 | 8 | Proband | F | 44 | NR | NS | 7 × ADCs | 4 × L858R, 2 × 19del, 1 × WT | The 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] |
| EGFR | p.T790 M | 11 | 9 | Proband | F | 34 | White | NS | ADC | L858R | Family history of lung and other cancers (paternal relatives); no germline EGFR T790 M status available in other members | Lou, et al. 2016 [42] |
| EGFR | p.R776H | 12 | 10 | Proband | F | 57 | White | NS | NSCLC | G719A | NSCLC with squamous component inside. Only a brother detected and did not carry the germline R776H mutation. | Van Noesel, et al. 2013 [43] |
| 13 | 10 | Daughter | F | 36 | White | NS | SCC | G719S | ||||
| EGFR | p.V769 M | 14 | 11 | Proband | M | 57 | Jewish | S | 5 × ADCs | 2 × G719A, 2 × (G719C + S768I), 1 × G719S | Family 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 postoperatively | Hellman, et al. 2017 [44] |
| EGFR | p.V843I | 15 | 12 | Proband | F | 70 | Asian | UK | 3 ADCs + 4 BACs + 3 AAHs | 3 × 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] |
| EGFR | p.V843I | 16 | 13 | Proband | F | 78 | Asian | UK | ADC | L858R | Aunt 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] |
| 17 | 13 | Mother | F | 70 | Asian | UK | ADC | L858R | ||||
| 18 | 13 | Brother | M | 41 | Asian | UK | ADC | L858R | ||||
| EGFR | p.V834 L | 19 | 14 | Proband | F | 57 | Surinam | S | ADC | L858R | A daughter carried germline V834 L; Father died of massive hemoptysis of unknown cause. | Van der Leest, et al. 2018 [47] |
| 20 | 14 | Brother | M | 57 | Surinam | S | NSCLC | L858R | ||||
| 21 | 14 | Sister | F | 46 | Surinam | NS | NSCLC | L858R | ||||
| 22 | 14 | Daughter | F | 42 | Surinam | NS | NSCLC | L858R | ||||
| HER2 | p.G660D | 23 | 15 | Proband | F | 44 | Asian | LS | Multi-ADCs | WT | HER2 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] |
| 24 | 15 | Mother | F | 74 | Asian | NS | Multi-ADCs | WT | ||||
| MET | p.N375K | 25 | 16 | Proband | F | 75 | Asian | NS | ADC | L858R | Another sister (never-smoker) clinically diagnosed with lung cancer at 80. | Tode, et al. 2017 [49] |
| 26 | 16 | Sister | F | 63 | Asian | NS | ADC | 19del | ||||
| 27 | 16 | Sister | F | 63 | Asian | LS | ADC | L858R | ||||
| CHEK2 | p.R474C (homozygous) | 28 | 17 | Proband | M | 60 | Asian | NS | Multi-ADCs, | NR | Proband: 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] |
| 29 | 17 | Sister | F | 60 | Asian | NS | 7 ADCs, | L858R or 19del | Uterine myoma and breast cancer affected | |||
| BRCA2 | c.9641insT | 30 | 18 | Proband | M | 43 | White | NS | ADC | Exon 20ins | Family history of breast cancer in maternal relatives and lung cancer in maternal grandfather (never smoker) | Marks, et al. 2008 [51] |
| BRCA2 | c.8867del5 | 31 | 19 | Proband | M | 74 | White | LS | ADC | 19del | Family history of breast or ovarian cancers in daughter, mother and maternal aunt. Daughter carried germline BRCA2 c.8867del5 mutation. | Marks, et al. 2008 [51] |
| TP53 | p.R273H | 32 | 20 | Proband | F | 34 | NR | NS | ADC | 19del | Proband: 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] |
| TP53 | p.G245S | 33 | 21 | Proband | F | 43 | Hispanic | NS | ADC | L858R | Concurrent 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] |
| TP53 | exon 19 deletion | 34 | 22 | Proband | F | 51 | White | NS | ADC | L858R | Proband: 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] |
| TP53 | p.H179Y | 35 | 23 | Proband | M | 55 | NR | NS | ADC | 19del | T790 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] |
| TP53 | p.R273H | 36 | 24 | Proband | F | 57 | NR | NS | ADC | L858R | Affected 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] |
| TP53 | p.G245S | 37 | 25 | Proband | F | 30 | NR | NR | ADC | 19 del | Daughter affected with sarcoma at 10. Another two children are carriers. | Pathak, et al. 2018 [56] |
| TP53/CDH1 | p.R196a; CDH1 p.N570= | 38 | 26 | Proband | F | 26 | Hispanic | NS | 3 ADC | 1 × 19del | Proband: 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] |
| TP53 | p.R248W | 39 | 27 | Proband a | F | 34 | NR | NS | 2 ADC | 1 × exon 20ins | The 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/PMS2 | p.V157D/ p.R20Q | 40 | 28 | Proband | M | 22 | Asian | NR | ADC | 19del | Family 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 mutations | Wang, et al. 2014 [59] |
| APC | c.TCA1110TGA | 41 | 29 | Proband | F | 43 | Asian | NS | ADC | WT | No 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] |
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
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