Germline mutations in lung cancer

Shukuya, Takehito; Takahashi, Kazuhisa

doi:10.1016/j.resinv.2018.12.005

Cited by 12 publications

(8 citation statements)

References 44 publications

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“…We identified 26.74% of lung cancer patients in this study who had at least one immediate family member with lung cancer. However, unlike other hereditary tumors, most of these lung cancer patients did not had clear pathogenic germline mutations, and the germline mutations or susceptibility loci of the families reported in the previous cases varied greatly, and no clear genetic abnormalities or aggregation has been identified (17,19,20). Therefore, it can be speculated that the occurrence of familial lung cancer may be due to a combination of multiple genetic factors and environmental factors.…”

Section: Discussionmentioning

confidence: 92%

The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility

Liu¹,

Liu²,

Suo³

et al. 2020

Transl Lung Cancer Res

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Background: Germline variations may contribute to lung cancer susceptibility besides environmental factors. The influence of germline mutations on lung cancer susceptibility and their correlation with somatic mutations has not been systematically investigated.Methods: In this study, germline mutations from 1,026 non-small cell lung cancer (NSCLC) patients were analyzed with a 58-gene next-generation sequencing (NGS) panel containing known hereditary cancerrelated genes, and were categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes.Results: Plausible genetic susceptibility was found in 4.7% of lung cancer patients, in which 14 patients with pathogenic mutations (P group) and 34 patients with likely-pathogenic mutations (LP group) were identified. The ratio of the first degree relatives with lung cancer history of the P groups was significantly higher than the Non-P group (P=0.009). The ratio of lung cancer patients with history of other cancers was higher in P (P=0.0007) or LP (P=0.017) group than the Non-P group. Pathogenic mutations fell most commonly in BRCA2, followed by CHEK2 and ATM. Likely-pathogenic mutations fell most commonly in NTRK1 and EXT2, followed by BRIP1 and PALB2. These genes are involved in DNA repair, cell cycle regulation and tumor suppression. By comparing the germline mutation frequency from this study with that from the whole population or East Asian population (gnomAD database), we found that the overall odds ratio (OR) for P or LP group was 17.93 and 15.86, respectively, when compared with the whole population, and was 2.88 and 3.80, respectively, when compared with the East Asian population, suggesting the germline mutations of the P and LP groups were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in tumor mutation burden (TMB) among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation frequency of TP53 in the P group was significantly lower than the other two groups, and the copy number variation (CNV) mutation frequency of PIK3CA and MET was significantly higher than the Non-P group. Pathway enrichment analysis found no significant difference in aberrant pathways among the three groups.Conclusions: A proportion of 4.7% of patients carrying germline variants may be potentially linked to increased susceptibility to lung cancer. Patients with pathogenic germline mutations exhibited stronger family history and higher lung cancer risk.

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Section: Discussionmentioning

confidence: 92%

The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility

Liu¹,

Liu²,

Suo³

et al. 2020

Transl Lung Cancer Res

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“…The data were also interrogated for coding variants in genes previously implicated in familial lung cancer (including EGFR, ERBB2, TP53 and PARK2 ) ( 26 ). Seventeen variants were identified, but the only two good-quality coding variants failed to segregate appropriately.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, none of the loci associated with lung cancer in the many GWAS to date include EGFR or other ERBB family members ( 3 ). The germline mutational profile of lung cancer was recently reviewed: few other genes have been reported with germline mutations in individuals with lung cancer ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

Germline ERBB3 mutation in familial non-small-cell lung carcinoma: expanding ErbB’s role in oncogenesis

McInerney-Leo

Chew

Inglis

et al. 2021

Human Molecular Genetics

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Introduction Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Materials and Methods Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and sub-cellular localisation were assessed, and cellular proliferation, pAkt/Akt, and pERK levels determined. Results A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80kD form (which enhances proliferation) compared to the full-length (180kD) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localisation pre- and post-EGF stimulation; however, EGFR levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared to wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 minutes post-stimulation compared to wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic. Conclusions This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.

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“…Germline alterations in DNA repair genes have previously been implicated as a risk factor for lung cancer by multiple groups. 36 For instance, in a large study that used cell-free DNA testing on a limited gene panel and reported incidental germline alterations in 0.7% (33 of 4, 459) of patients with lung cancer, mutations in BRCA2 were the most frequent (17 of 33 patients). 37 Similar results were also reported by Mukherjee et al, 38 who observed an increased frequency of germline alterations in patients with lung cancer with a family history of other cancers, early age at onset, or carrying a diagnosis of multiple cancers.…”

Section: Discussionmentioning

confidence: 99%

Genomic Profiling of Lung Adenocarcinoma in Never-Smokers

Devarakonda

Rodrigues

et al. 2021

JCO

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PURPOSE Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. METHODS We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. RESULTS We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P < .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. CONCLUSION In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.

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Germline mutations in lung cancer

Cited by 12 publications

References 44 publications

The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility

The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility

Germline ERBB3 mutation in familial non-small-cell lung carcinoma: expanding ErbB’s role in oncogenesis

Genomic Profiling of Lung Adenocarcinoma in Never-Smokers

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