Elevated incidence of somatic mutations at prevalent genetic sites

Author:

Wang Mengyao12ORCID,Li Shuai Cheng1ORCID,Shen Bairong345ORCID

Affiliation:

1. Department of Computer Science, City University of Hong Kong , 83 Tat Chee Ave, Kowloon Tong, Hong Kong , China

2. Laboratory of Gastrointestinal Cancer (Fujian Medical University) , Ministry of Education, Fuzhou , China

3. Institutes for Systems Genetics , Frontiers Science Center for Disease-Related Molecular Network, , Chengdu, Sichuan , China

4. West China Hospital, Sichuan University , Frontiers Science Center for Disease-Related Molecular Network, , Chengdu, Sichuan , China

5. Joint Laboratory of Artificial Intelligence for Critical Care Medicine , Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610212, Chengdu , China

Abstract

Abstract The common loci represent a distinct set of the human genome sites that harbor genetic variants found in at least 1% of the population. Small somatic mutations occur at the common loci and non-common loci, i.e. csmVariants and ncsmVariants, are presumed with similar probabilities. However, our work revealed that within the coding region, common loci constituted only 1.03% of all loci, yet they accounted for 5.14% of TCGA somatic mutations. Furthermore, the small somatic mutation incidence rate at these common loci was 2.7 times that observed in the non-common. Notably, the csmVariants exhibited an impressive recurrent rate of 36.14%, which was 2.59 times of the ncsmVariants. The C-to-T transition at the CpG sites accounted for 32.41% of the csmVariants, which was 2.93 times for the ncsmVariants. Interestingly, the aging-related mutational signature contributed to 13.87% of the csmVariants, 5.5 times that of ncsmVariants. Moreover, 35.93% of the csmVariants contexts exhibited palindromic features, outperforming ncsmVariant contexts by 1.84 times. Notably, cancer patients with higher csmVariants rates had better progression-free survival. Furthermore, cancer patients with high-frequency csmVariants enriched with mismatch repair deficiency were also associated with better progression-free survival. The accumulation of csmVariants during cancerogenesis is a complex process influenced by various factors. These include the presence of a substantial percentage of palindromic sequences at csmVariants sites, the impact of aging and DNA mismatch repair deficiency. Together, these factors contribute to the higher somatic mutation incidence rates of common loci and the overall accumulation of csmVariants in cancer development.

Funder

CityU Strategic Interdisciplinary Research Grant

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

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