Estimating the predictive power of silent mutations on cancer classification and prognosis

Abstract

In recent years it has been shown that silent mutations, in and out of the coding region, can affect gene expression and may be related to tumorigenesis and cancer cell fitness. However, the predictive ability of these mutations for cancer type diagnosis and prognosis has not been evaluated yet. In the current study, based on the analysis of 9,915 cancer genomes and approximately three million mutations, we provide a comprehensive quantitative evaluation of the predictive power of various types of silent and non-silent mutations over cancer classification and prognosis. The results indicate that silent-mutation models outperform the equivalent null models in classifying all examined cancer types and in estimating the probability of survival 10 years after the initial diagnosis. Additionally, combining both non-silent and silent mutations achieved the best classification results for 68% of the cancer types and the best survival estimation results for up to nine years after the diagnosis. Thus, silent mutations hold considerable predictive power over both cancer classification and prognosis, most likely due to their effect on gene expression. It is highly advised that silent mutations are integrated in cancer research in order to unravel the full genomic landscape of cancer and its ramifications on cancer fitness.

Hairy cell leukaemia with unusual BRAF mutations

“…Synonymous mutations do not change the amino acid sequence and most of them are expected to be functionally neutral. The clinical impact of synonymous mutations remains to be specified but they can change protein levels or protein conformation by altering splicing regulatory sites, mRNA stability, miRNA binding sites or translation efficiency 17 . Either in or out of the coding regions, they can affect gene expression and may be contribute to tumorigenesis and cancer‐cell fitness 18 .…”

IL22RA1/JAK/STAT Signaling Acts As a Cancer Target Through Pan-Cancer Analysis

“…Gene alterations lead to cancer initiation and driving progression (32). Silent mutations can affect gene expression which may relate to tumorigenesis and cancer cell fitness (33). It is worth to note that the non-silent mutation rate of IL22RA1 is high in UCEC and SKCM compared with the other types of cancer.…”

FASN, SCD1 and ANXA9 gene polymorphism as genetic predictors of the fatty acid profile of sheep milk

“…Mutations in regulatory regions such as promoters or enhancers can disrupt or create new transcription factor binding sites and cause changes in transcription regulation. Mutations in untranslated regions may affect the regulation of translation or modify the microRNA binding sites and thus affect mRNA stability 37 . The polymorphism analyzed in the FASN gene is an exon mapped change and it is a synonymous mutation.…”

“…In general, silent mutations can modify all phases of the gene expression process, resulting in the amplification or reduction of proteins concentration. Therefore, while most silent mutations do not alter protein functionality, they can dramatically alter protein abundance 37 . In many cases, the effect of the SNP polymorphism rather regulate gene expression than changing the amino acid sequence as was shown by Knutsen et al in bovine 39 .…”