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A substantial proportion of apparently heterozygous TP53 pathogenic variants detected with a next-generation sequencing hereditary pan-cancer panel are acquired somatically.

ABSTRACT: Previous analysis of next-generation sequencing (NGS) hereditary pan-cancer panel testing demonstrated that approximately 40% of TP53 pathogenic and likely pathogenic variants (PVs) detected have NGS allele frequencies between 10% and 30%, indicating that they likely are acquired somatically. These are seen more frequently in older adults, suggesting that most result from normal aging-related clonal hematopoiesis. For this analysis, apparent heterozygous germline TP53 PV carriers (NGS allele frequency 30-70%) were offered follow-up testing to confirm variant origin. Ninety-eight probands had samples submitted for follow-up family member testing, fibroblast testing, or both. The apparent heterozygous germline TP53 PV was not detected in 32.6% (15/46) of submitted fibroblast samples, indicating that it was acquired somatically, either through clonal hematopoiesis or via constitutional mosaicism. Notably, no individuals with confirmed germline or likely germline TP53 PVs met classic Li-Fraumeni syndrome (LFS) criteria, only 41% met Chompret LFS criteria, and 59% met neither criteria, based upon provider-reported personal and family cancer history. Comprehensive reporting of TP53 PVs detected using NGS, combined with follow-up analysis to confirm variant origin, is advised for clinical testing laboratories. These findings underscore the investment required to provide individuals and family members with clinically accurate genetic test results pertaining to their LFS risk.

SUBMITTER: Coffee B

PROVIDER: S-EPMC6972517 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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A substantial proportion of apparently heterozygous TP53 pathogenic variants detected with a next-generation sequencing hereditary pan-cancer panel are acquired somatically.

Coffee Bradford B Cox Hannah C HC Bernhisel Ryan R Manley Susan S Bowles Karla K Roa Benjamin B BB Mancini-DiNardo Debora D

Human mutation 20190923 1

Previous analysis of next-generation sequencing (NGS) hereditary pan-cancer panel testing demonstrated that approximately 40% of TP53 pathogenic and likely pathogenic variants (PVs) detected have NGS allele frequencies between 10% and 30%, indicating that they likely are acquired somatically. These are seen more frequently in older adults, suggesting that most result from normal aging-related clonal hematopoiesis. For this analysis, apparent heterozygous germline TP53 PV carriers (NGS allele fre ...[more]

PMID: 31490007

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Project description:BackgroundIn recent years, research on cancer predisposition germline variants has emerged as a prominent field. The identity of somatic mutations is based on a reliable mapping of the patient germline variants. In addition, the statistics of germline variants frequencies in healthy individuals and cancer patients is the basis for seeking candidates for cancer predisposition genes. The Cancer Genome Atlas (TCGA) is one of the main sources of such data, providing a diverse collection of molecular data including deep sequencing for more than 30 types of cancer from >?10,000 patients.MethodsOur hypothesis in this study is that whole exome sequences from blood samples of cancer patients are not expected to show systematic differences among cancer types. To test this hypothesis, we analyzed common and rare germline variants across six cancer types, covering 2241 samples from TCGA. In our analysis we accounted for inherent variables in the data including the different variant calling protocols, sequencing platforms, and ethnicity.ResultsWe report on substantial batch effects in germline variants associated with cancer types. We attribute the effect to the specific sequencing centers that produced the data. Specifically, we measured 30% variability in the number of reported germline variants per sample across sequencing centers. The batch effect is further expressed in nucleotide composition and variant frequencies. Importantly, the batch effect causes substantial differences in germline variant distribution patterns across numerous genes, including prominent cancer predisposition genes such as BRCA1, RET, MAX, and KRAS. For most of known cancer predisposition genes, we found a distinct batch-dependent difference in germline variants.ConclusionTCGA germline data is exposed to strong batch effects with substantial variabilities among TCGA sequencing centers. We claim that those batch effects are consequential for numerous TCGA pan-cancer studies. In particular, these effects may compromise the reliability and the potency to detect new cancer predisposition genes. Furthermore, interpretation of pan-cancer analyses should be revisited in view of the source of the genomic data after accounting for the reported batch effects.

Dataset Information

A substantial proportion of apparently heterozygous TP53 pathogenic variants detected with a next-generation sequencing hereditary pan-cancer panel are acquired somatically.

Publications

A substantial proportion of apparently heterozygous TP53 pathogenic variants detected with a next-generation sequencing hereditary pan-cancer panel are acquired somatically.

Similar Datasets

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