Centenarian Exomes as a Tool for Evaluating the Clinical Relevance of Germline Tumor Suppressor Mutations

Abstract

Objectives: The aim of the present study was to evaluate the clinical relevance of mutations in tumor suppressor genes using whole-exome sequencing data from centenarians and young healthy individuals. Methods: Two pools, one of centenarians and one of young individuals, were constructed and whole-exome sequencing was performed. We examined the whole-exome sequencing data of Bulgarian individuals for carriership of tumor suppressor gene variants. Results: Of all variants annotated in both pools, 5080 (0.06%) are variants in tumor suppressor genes but only 46 show significant difference in allele frequencies between the two studied groups. Four variants (0.004%) are pathogenic/risk factors according to single nucleotide polymorphism database: rs1566734 in PTPRJ, rs861539 in XRCC3, rs203462 in AKAP10, and rs486907 in RNASEL. Discussion: Based on their high minor allele frequencies and presence in the centenarian group, we could reclassify them from pathogenic/risk factors to benign. Our study shows that centenarian exomes can be used for re-evaluating the clinically uncertain variants.

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…A meta-analysis of the various data obtained ( Laczmanska and Sasiadek, 2019 ) fueled correspondence ( Gholami and M MA, 2019 ) that in the end ( Laczmanska and Sasiadek, 2020 ) led to the conclusion that the p.Q276P polymorphism is not associated with increased cancer risks and that the link for p.R326Q with colorectal cancer susceptibility is biased by data from a single study and thus awaiting independent confirmation. In fact this is echoed by results from a recent whole-exome sequencing project aimed at evaluating the clinical relevance of tumor suppressor gene variants, which illustrated the need for a careful classification of SNP effects ( Balabanski et al, 2020 ). For example, rs1566734 in PTPRJ is listed as risk factor in SNP databases but its high minor allele frequency and its presence among centenarians rather points to a benign nature.…”

Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein

“…Globally, the number of long-living adults (aged 90 years and older) has been increasing dramatically. These individuals exhibit a degree of genetic homogeneity and rarely carry pathogenic gene variants associated with the early onset of life-threatening diseases, including cognitive impairment (CI) (Balabanski et al, 2020). Therefore, examining their genetic makeup could provide valuable insights into the underlying mechanisms of CI.…”

The effects of CD148 Q276P/R326Q polymorphisms in A431D epidermoid cancer cell proliferation and epidermal growth factor receptor signaling

“… 29 , 35 On the other hand, several studies have shown that Q276P and/or R326Q genotype show no impacts on human cancer risks, including colon, breast, and thyroid cancers. 35 , 36 , 37 , 38 , 39 Thus, conflicting results were also reported with these polymorphisms. It was recently shown that the haplotype impacts whether the polymorphism confers a cancer risk.…”

“…Interestingly, Q276P and R326Q were shown to be in perfect linkage disequilibrium 29,35 . On the other hand, several studies have shown that Q276P and/or R326Q genotype show no impacts on human cancer risks, including colon, breast, and thyroid cancers 35–39 . Thus, conflicting results were also reported with these polymorphisms.…”