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Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer.

ABSTRACT: In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline variant predisposing to cancer and a further eleven patients carried a prioritized VUS with a strong association to the cancerogenesis of the patient. Through clinical screening, 51 patients (31.3%) were identified as suspicious for an underlying cancer predisposition syndrome (CPS), but only in ten of those patients a pathogenic variant could be identified. In contrast, one patient with a classical CPS and ten patients with prioritized VUS were classified as unremarkable in the clinical work-up. Taken together, a monogenetic causative variant was detected in 13.8% of our patients using WES. Nevertheless, the still unclarified clinical suspicious cases emphasize the need to consider other genetic mechanisms including new target genes, structural variants, or polygenic interactions not previously associated with cancer predisposition.

SUBMITTER: Wagener R

PROVIDER: S-EPMC8385053 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer.

Wagener Rabea R Taeubner Julia J Walter Carolin C Yasin Layal L Alzoubi Deya D Bartenhagen Christoph C Attarbaschi Andishe A Classen Carl-Friedrich CF Kontny Udo U Hauer Julia J Fischer Ute U Dugas Martin M Kuhlen Michaela M Borkhardt Arndt A Brozou Triantafyllia T

European journal of human genetics : EJHG 20210412 8

In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline var ...[more]

PMID: 33840814

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Project description: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.

Project description:BackgroundGermline mutations in numerous genes, particularly tumor suppressor genes, markedly heighten the risk of various cancers, including lung cancer, which is the leading cause of cancer-related deaths worldwide. Despite extensive research on well-known genes like BRCA1, BRCA2, and mismatch repair genes, many genetic factors contributing to cancer susceptibility remain unidentified.MethodsThis study reviewed sequencing data from 4,934 Chinese lung cancer patients. Matched white blood cell samples were sequenced using WES or gene panels to identify germline mutations. Analysis included statistical tests to compare patient demographics, clinical characteristics, and somatic mutation profiles.ResultsAmong the cohort, 89 patients carried pathogenic/likely pathogenic (P/LP) germline mutations in 20 known cancer susceptibility genes, with ATM, BRCA2, and CHEK2 being the most common. TP53 mutations were linked to early-onset lung cancer, while ATM mutations correlated with late-onset and higher PD-L1 expression, suggesting immunotherapy benefits. Germline mutations were more prevalent in younger patients and females. Somatic mutation profiles showed similarities in common mutations but differences in MTOR (p = 0.044) and MSH6 (p = 0.018) mutations in P/LP carriers. GO and KEGG analyses indicated distinct biological processes and pathways in patients with P/LP germline mutations. Gene exclusivity analysis revealed correlations and mutual exclusivity between specific germline and somatic mutations. Comparative analysis with the gnomAD database showed a higher prevalence of these mutations in lung cancer patients compared to the general and East Asian populations, suggesting an association with increased lung cancer risk in the Chinese cohort.ConclusionThis study underscores the prevalence of germline mutations in Chinese lung cancer patients, identifying significant associations with clinical characteristics and somatic mutation profiles. The findings highlight the importance of considering germline mutations in lung cancer treatment and the potential benefits of personalized therapy based on genetic susceptibility.

Dataset Information

Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer.

Publications

Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer.

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