DNA Mismatch Repair Gene Variants in Sporadic Solid Cancers

Abstract

The phenotypic effects of single nucleotide polymorphisms (SNPs) in the development of sporadic solid cancers are still scarce. The aim of this review was to summarise and analyse published data on the associations between SNPs in mismatch repair genes and various cancers. The mismatch repair system plays a unique role in the control of the genetic integrity and it is often inactivated (germline and somatic mutations and hypermethylation) in cancer patients. Here, we focused on germline variants in mismatch repair genes and found the outcomes rather controversial: some SNPs are sometimes ascribed as protective, while other studies reported their pathological effects. Regarding the complexity of cancer as one disease, we attempted to ascertain if particular polymorphisms exert the effect in the same direction in the development and treatment of different malignancies, although it is still not straightforward to conclude whether polymorphisms always play a clear positive role or a negative one. Most recent and robust genome-wide studies suggest that risk of cancer is modulated by variants in mismatch repair genes, for example in colorectal cancer. Our study shows that rs1800734 in MLH1 or rs2303428 in MSH2 may influence the development of different malignancies. The lack of functional studies on many DNA mismatch repair SNPs as well as their interactions are not explored yet. Notably, the concerted action of more variants in one individual may be protective or harmful. Further, complex interactions of DNA mismatch repair variations with both the environment and microenvironment in the cancer pathogenesis will deserve further attention.

The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

“…The authors concluded that oxidative DNA damage along with TP53 mutation are important contributors to colorectal adenoma–carcinoma transition [ 82 ]. Apart from somatic mutations in the gene, polymorphic features (germline variants including single nucleotide polymorphisms) of the gene may also modulate its function [ 83 ]. Wang et al investigated germline variants in ATR/CHEK1 and ATM/CHEK2 (rs35514263 in ATR ; rs492510, rs558351 in CHKE1 ; rs189037 in ATM ; rs2236141, rs5762748, rs2236142, and rs9620817 in CHEK2 ) acting in DDR and their association with CRC risk in a Chinese population.…”

Evaluation of global and intragenic hypomethylation in colorectal adenomas improves patient stratification and colorectal cancer risk prediction

“…Transversions on KRAS oncogene have been recognized as the hallmark of increased oxidative DNA damage due to the overproduction of ROS, normally involved in many redox-governing processes of the cells [ 36 ]. BER pathway is the main mechanism controlling the removal and repair of oxidized DNA bases.…”

Aggresome–Autophagy Associated Gene HDAC6 Is a Potential Biomarker in Pan-Cancer, Especially in Colon Adenocarcinoma

“…Under normal circumstances, mismatches may occur during DNA replication, leading to genetic mutations, but regulation by the MMR genome in cells can identify and correct mutations (44). Moreover, mutations in the MMR genome can exacerbate the increased accumulation of genetic errors causing genomic instability or MSI (45). DNA methylation is an essential factor leading to altered tumor development, and an increasing number of studies show that hypermethylation of gene promoters is a common epigenetic feature of cancer (46).…”