Dataset Information

Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

ABSTRACT: BACKGROUND:Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes. RESULTS:We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR?=?0.00188). In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR?=?0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR?=?0.00615) and the AID/APOBEC-related mutational processes (FDR?=?8.69?×?10-?4). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR?

SUBMITTER: Guo J

PROVIDER: S-EPMC6048762 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

Guo Jintao J Huang Jiankun J Zhou Ying Y Zhou Yulin Y Yu Liying L Li Huili H Hou Lingyun L Zhu Liuwei L Ge Dandan D Zeng Yuanyuan Y Guleng Bayasi B Li Qiyuan Q

BMC genomics 20180716 1

<h4>Background</h4>Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes.<h4>Results</h4>We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes ba ...[more]

PMID: 30012096

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Project description:BackgroundThe mutational profile of cancer reflects the activity of the mutagenic processes which have been operative throughout the lineage of the cancer cell. These processes leave characteristic profiles of somatic mutations called mutational signatures. Mutational signatures, including single-base substitution (SBS) signatures, may reflect the effects of exogenous or endogenous exposures.MethodsWe used polygenic risk scores (PRS) to summarize common germline variation associated with cancer risk and other cancer-related traits and examined the association between somatic mutational profiles and germline PRS in 12 cancer types from The Cancer Genome Atlas. Somatic mutational profiles were constructed from whole-exome sequencing data of primary tumors. PRS were calculated for the 12 selected cancer types and 9 non-cancer traits, including cancer risk determinants, hormonal factors, and immune-mediated inflammatory diseases, using germline genetic data and published summary statistics from genome-wide association studies.ResultsWe found 17 statistically significant associations between somatic mutational profiles and germline PRS after Bonferroni correction (p < 3.15 × 10-5), including positive associations between germline inflammatory bowel disease PRS and number of somatic mutations attributed to signature SBS1 in prostate cancer and APOBEC-related signatures in breast cancer. Positive associations were also found between age at menarche PRS and mutation counts of SBS1 in overall and estrogen receptor-positive breast cancer. Consistent with prior studies that found an inverse association between the pubertal development PRS and risk of prostate cancer, likely reflecting hormone-related mechanisms, we found an inverse association between age at menarche PRS and mutation counts of SBS1 in prostate cancer. Inverse associations were also found between several cancer PRS and tumor mutation counts.ConclusionsOur analysis suggests that there are robust associations between tumor somatic mutational profiles and germline PRS. These may reflect the mechanisms through hormone regulation and immune responses that contribute to cancer etiology and drive cancer progression.

Dataset Information

Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

Publications

Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

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