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

Cheng, Yue I.; Gan, Yun Cui; Liu, Dan; Davies, Michael P. A.; Li, Wei Min; Field, John K.

doi:10.1186/s12885-019-6317-6

BMC Cancer

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 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.	Tibaldi, et al. 2011 [38]
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		Van Noesel, et al. 2013 [43]
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.R196^a; 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

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