Dataset Information

Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients.

ABSTRACT: Hepatoblastoma is a very rare embryonal liver cancer supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. In this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. Our data disclosed a low mutational background and pointed out to a novel set of candidate genes for hepatoblastoma biology, which were shown to impact gene expression levels. Only three recurrently mutated genes were detected: CTNNB1 and two novel candidates, CX3CL1 and CEP164. A relevant finding was the identification of a recurrent mutation (A235G) in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed upregulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 pathway occurs in hepatoblastomas. In inflammatory regions of hepatoblastomas, CX3CL1/CX3CR1 were not detected in the infiltrated lymphocytes, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative labeling in tumor cells, but strongly positive infiltrated lymphocytes. Altogether, these data suggested that CX3CL1/CX3CR1 upregulation may be a common feature of hepatoblastomas, potentially related to chemotherapy response and progression. In addition, three mutational signatures were identified in hepatoblastomas, two of them with predominance of either the COSMIC signatures 1 and 6, found in all cancer types, or the COSMIC signature 29, mostly related to tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C>A mutations. Overall, we present here novel candidate genes for hepatoblastoma, with evidence that CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with progression, besides reporting specific mutational signatures.

SUBMITTER: Aguiar TFM

PROVIDER: S-EPMC7214543 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients.

Aguiar Talita Ferreira Marques TFM Rivas Maria Prates MP Costa Silvia S Maschietto Mariana M Rodrigues Tatiane T Sobral de Barros Juliana J Barbosa Anne Caroline AC Valieris Renan R Fernandes Gustavo R GR Bertola Debora R DR Cypriano Monica M Caminada de Toledo Silvia Regina SR Major Angela A Tojal Israel I Apezzato Maria Lúcia de Pinho MLP Carraro Dirce Maria DM Rosenberg Carla C Lima da Costa Cecilia Maria CM Cunha Isabela W IW Sarabia Stephen Frederick SF Terrada Dolores-López DL Krepischi Ana Cristina Victorino ACV

Frontiers in oncology 20200505

Hepatoblastoma is a very rare embryonal liver cancer supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. In this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. Our data disclosed a low mutational background and pointed out to a novel set of candidate genes for hepatoblastoma biology, which were shown to impact gene expression levels. Only three recurrently mutated gen ...[more]

PMID: 32432034

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Project description:Genome-wide association studies have reported nearly 100 common germline susceptibility loci associated with the risk for breast cancer. Tumour sequencing studies have characterised somatic mutation profiles in breast cancer patients. The relationship between breast cancer susceptibility loci and somatic mutation patterns in breast cancer remains largely unexplored.We used single-nucleotide polymorphism (SNP) genotyping array data and tumour exome sequencing data available from 638 breast cancer patients of European ancestry from The Cancer Genome Atlas (TCGA) project. We analysed both genotype data and, when necessary, imputed genotypes for 90 known breast cancer susceptibility loci. We performed linear regression models to investigate possible associations between germline risk variants with total somatic mutation count (TSMC), as well as specific mutation types. We examined individual SNP genotypes, as well as a multi-SNP polygenic risk score (PRS). Models were statistically adjusted for age at diagnosis, stage, oestrogen-receptor (ER) and progesterone-receptor (PR) status of breast cancer. We also performed stratified analyses by ER and PR status.We observed a significant inverse association (P=8.75 × 10(-6); FDR=0.001) between the risk allele in rs2588809 of the gene RAD51B and TSMC across all breast cancer patients, for both ER(+) and ER(-) tumours. This association was also evident for different types of mutations. The PRS analysis for all patients, with or without rs2588809, showed a significant inverse association (P=0.01 and 0.04, respectively) with TSMC. This inverse association was significant in ER(+) patients with the ER(+)-specific PRS (P=0.02), but not among ER(-) patients for the ER(-)-specific PRS (P=0.39).We observed an inverse association between common germline risk variants and TSMC, which, if confirmed, could provide new insights into how germline variation informs our understanding of somatic mutation patterns in breast cancer.

Dataset Information

Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients.

Publications

Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients.

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