Elsevier

Current Problems in Cancer

Volume 41, Issue 4, July–August 2017, Pages 251-264
Current Problems in Cancer

Inherited mutations in DNA repair genes and cancer risk

https://doi.org/10.1016/j.currproblcancer.2017.02.009Get rights and content

Abstract

Although most cancer cases are due to somatic mutations, up to 10% of cases are attributable to germline mutations. This inherited cancer predisposition is mostly due to the loss of function of suppressor genes rather than the activation of oncogenes. Defects in DNA repair genes are the genetic events most commonly involved in hereditary cancers. The implementation of high-throughput sequencing in diagnostic testing has uncovered new predisposition genes. Furthermore, for some tumor types these sequencing techniques have also unveiled a prevalence of germline mutations significantly higher than previous estimations. The clinical implications of many of these repair defects are yet to be defined. Further studies will need to be conducted to establish the most appropriated management of unaffected carriers that are likely to grow in numbers. On the contrary, the presence of DNA repair defects provides a unique opportunity for the development of treatments that take advantage of a tumor feature.

In this review article, we summarize not only the most common syndromes linked to DNA repair defects but also less known entities. We address the underlying genetics and the clinical implications of each DNA repair defect as well as the current recommendations for cancer surveillance.

Introduction

Cancers develop as a result of mutations in certain genes that impair the cells ability to grow and divide properly. For most common cancers, the genetic lesions that promote tumorigenesis are acquired somatically and do not involve germline alterations. However, 5%-10% of cancers result from inherited abnormalities. In these cases, cancer predisposition is mostly due to the loss of function of suppressor genes rather than the activation of oncogenes, and defects in DNA repair genes are the genetic events most commonly involved in hereditary cancers. A single defective copy of a gene is typically inherited and transformation requires somatic loss of the second wild-type allele. The rate of somatic loss of a single allele is significantly higher than the independent mutation of 2 alleles and in consequence the incidence of specific cancers in mutation carriers is higher than that of general population.1

Alterations in the mismatch repair (MMR), base excision repair, double-strand break repair (DSB), and nucleotide excision repair (NER) systems have been described to underlie several cancer predisposition syndromes. The implementation of high-throughput sequencing in diagnostic testing has uncovered new predisposition genes, but it has also awaked new challenges in the daily clinical practice of oncologists that are suddenly involved in the scenario of classical genetic counseling.

Here, we will review not only the most common syndromes linked to DNA repair defects such as the hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS) but also less known entities (Table 1). We will address the underlying genetics and the clinical implications of each defect as well as the current recommendations for cancer surveillance.

Section snippets

Hereditary breast and ovarian cancer syndromes

Breast cancer is the most prevalent type of cancer in women in the developed countries.2 However, only 5%-10% of these tumors are due to specific mutations that are passed down in a family when unselected women are considered, rising to 20% if a family history of the disease is present. Heritage has a greater effect for ovarian cancer as mutations in cancer susceptibility genes have been described to be present in 1 of 5 women affected.3, 4

Most HBOCs can be ascribed to highly penetrant germline

Mismatch repair system defects: Lynch syndrome

A distinct pathway for DNA repair is subject to cancer-associated mutations in LS, or hereditary nonpolyposis CRC. LS is an autosomal dominant disorder, caused by a germline mutation in one of the several genes involved in MMR. The 4 most commonly mutated genes, MLH1, MSH2, MSH6, and PMS2, encode proteins that recognize incorrectly paired nucleotides and erroneous insertions or deletions that also cause helix distortion.71 This is of special relevance during the replication of simple repetitive

Base excision repair: MUTYH gene

MUTYH gene codifies a glycosylase involved in base excision DNA repair, mostly correcting oxidative damage. Cellular metabolism causes guanine to be altered by oxygen and subsequently pairs it with adenine instead of cytosine. MYH glycosylase corrects this mistake and a faulty or absent protein is responsible for 7% of familial adenomatous polyposis and up to 40% of attenuated polyposis variants.100

Although it has been considered as a recessive genetic disease, current evidence shows that both

Nucleotide excision repair: Xeroderma pigmentosum

Xeroderma pigmentosum is a group of genetic disorders with an estimated prevalence of 1:1,000,000 in occidental countries, with higher rates reported in North Africa and Japanese population.109, 110 It is characterized by an inherited hypersensitivity to the DNA-damaging effects of ultraviolet (UV) radiation, ocular abnormalities, and neurologic deficits. It is caused by pathogenic variants in components of the nucleotide excision repair (NER) system (XPA, XPC, DDB2, ERCC1, ERCC2, ERCC3, ERCC4,

Implications of genetic testing for germline mutations

The implementation of multitest panels in clinical practice to seek for actionable genetic aberrations has confronted oncologist with a new challenge, as they must deal with the incidental findings arising from these tests both in the somatic and in the germline. This is currently a hot topic not only for genetic counseling but also for medicine in general. Incidental findings are results unrelated to the indication for ordering the sequencing but of medical value for patient care. Although

Future directions

The implementation of high-throughput sequencing in diagnostic testing and in cancer clinics has not only uncovered new predisposition genes but has also allowed the identification of germline alterations in tumors thought to be sporadic. As an example, a recent study has identified germline mutations in DNA repair genes in up to 12% of metastatic prostate cancers when the previously estimated prevalence was 5%.118 With sequencing techniques becoming more widely available, it is very likely to

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