Profiling Oncogenic Germline Mutations in Unselected Chinese Lung Cancer Patients

Abstract

IntroductionEmerging evidence has suggested that inherited factors are also involved in lung cancer development. However, most studies focused on well-elucidated cancer predisposition genes, the majority of which are tumor suppressor genes. The profile of germline mutations in oncogenic driver genes remains unrevealed, which might also provide potential clinical implications for lung cancer management.MethodsSequencing data from 36,813 unselected lung cancer patients who underwent somatic mutation profiling were retrospectively reviewed. All recruited patients had matched white blood cell samples sequenced in parallel using a capture-based panel including eight key lung cancer driver genes (epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), MET proto-oncogene, receptor tyrosine kinase (MET), Kirsten rat sarcoma viral oncogene homolog (KRAS), Erb-B2 receptor tyrosine kinase 2(ERBB2), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), ret proto-oncogene (RET), and B-Raf proto-oncogene, serine/threonine kinase (BRAF)). Likely pathogenic/pathogenic (LP/P) variants were called according to the classification criteria of the American College of Medical Genetics and Genomics. Variants of uncertain significance (VUS) located in the kinase domains of driver genes and occurring recurrently (n ≥3) were also included for further analyses.ResultsSeven different LP/P variants in EGFR, MET, or RET were identified in 0.03% of lung cancer patients (n = 14) and 25 different VUS in the kinase domains of seven driver genes (except KRAS) were found with a prevalence of 0.3% (n = 117).Collectively, germline mutations were most frequently seen in ROS1 (n = 31, 0.084%), followed by MET (n = 23, 0.062%), EGFR (n = 22, 0.06%), ALK (n = 22, 0.06%) and RET (n = 17, 0.046%). LP/P variants and VUS fell the most commonly in EGFR (n = 10, 72%) and ROS1 (n = 31, 26%), respectively. Of the 10 patients with EGFR LP/P germline mutation, 70% also acquired somatic EGFR driver mutation exon21 p.L858R or exon19 deletion at baseline; while the three patients with pathogenic germline RET mutation displayed distinct baseline somatic profiles of rare EGFR mutation or KRAS exon2 p.G12C. We discovered 11 germline mutations that also occurred somatically, including four LP/P variants and seven VUS.ConclusionWe present the first study to systemically characterize the germline mutation in oncogenic driver genes in a large cohort of unselected patients with lung cancers.

Clinical application of liquid biopsy in cancer patients

“…In the current study, we identified a MUTYH germline mutation in one ovarian cancer patient. A previous study in 36,813 Chinese lung cancer patients, focusing on eight key lung cancer driver genes (EGFR, ALK, MET, KRAS, ERBB2, ROS1, RET, and BRAF), revealed a prevalence of 0.03% for P/LP germline mutations [30]. However, we did not find germline mutations in these genes.…”

Metabolomics and the Multi-Omics View of Cancer

“…For instance, with the advent of next generation sequencing (NGS), many large-scale surveys of known and suspected germline mutations in cancer patients have now been conducted. These surveys have provided even more exacting estimates of the true prevalence of heritable cancers [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Additionally, dozens of large-scale genome-wide association studies (GWAS) for many cancers have also been pursued.…”

“…These 12 types of cancer account for ~78% of all known cancer cases in the US [55], and therefore, the numbers generated from this analysis can be reasonably extrapolated to all cancer types. [20] 11.0 [41] 57 [18] Lung 235,760 [55] 0.3-1.4 [27][28][29] Ave. = 0.9 8.7 [20] 0.7 [42] 18 [18] Colorectal 149,500 [55] 3.5-7.5 [30,31] Ave. = 5.5 12.8 [20] 1.2 [43] 15 [18] Melanoma 106,110 [55] 1.9-3.1 [32,33] Ave. = 2.5 4.9 [20] 0.9 [44] 58 [18] Bladder 83,730 [55] 8.9 [34] 5.4 [20] 0.9 [45] 30 [18 1. First, the prevalence of heritable cancers derived from NGS analysis of high penetrance germline mutations (Table 1, Column 3, Germline Prevalence) varies much more than the traditional "5-10%" that is often quoted [16,17], indeed, it ranges from a low of 0.3% in lung cancer to a high of 17.2% in prostate cancer.…”

Identification of pathogenic germline variants in a large Chinese lung cancer cohort by clinical sequencing

“…For instance, germline mutations in BRAC2 were found to be associated with a higher risk and early onset of lung cancer in Chinese population [ 19 , 20 ]; however, such an association was not observed in several studies with European ancestry as study subjects [ 2 ], emphasizing the need to characterize the landscape of ethnicity‐specific harmful inherited genetic variations. Some studies have been conducted to pinpoint genes and loci associated with susceptibility to lung cancer in Chinese population [ 9 , 20 , 21 , 22 , 23 , 24 ]. Existing studies have some limitations such as small sample size, few covered genes, and lack of somatic mutation data, reducing the ability of finding rare germline variants and the exploration of the interaction between germline and somatic mutations.…”