Inherited mutations in DNA repair genes and cancer risk
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
References (119)
- et al.
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies
Am J Hum Genet
(2003) - et al.
Cumulative risk of second primary contralateral breast cancer in BRCA1/BRCA2 mutation carriers with a first breast cancer: a systematic review and meta-analysis
Breast
(2014) - et al.
Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer
Gynecol Oncol
(2011) - et al.
BRCA in breast cancer: ESMO Clinical Practice Guidelines
Ann Oncol
(2011) - et al.
Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility
Eur J Cancer
(2011) - et al.
Breast cancer in a RAD51D mutation carrier: case report and review of the literature
Clin Breast Cancer
(2015) - et al.
Hereditary ovarian cancer: beyond the usual suspects
Gynecol Oncol
(2012) - et al.
Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis
Eur J Cancer
(2010) Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis
Cancer Lett
(2006)Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis
Cancer Genet
(2011)
Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions
Ageing Res Rev
Mismatch repair: mechanisms and relationship to cancer susceptibility
Trends Biochem Sci
EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome
Genet Med
Genetics of hereditary colorectal cancer
Seminars in oncology
Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome
Gastroenterology
Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset
Gastroenterology
Better survival rates in patients with MLH1-associated hereditary colorectal cancer
Gastroenterology
Muir-Torre syndrome
Lancet Oncol
Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial
Lancet
American gastroenterological association institute guideline on the diagnosis and management of Lynch syndrome
Gastroenterology
DNA repair, genome stability and cancer: a historical perspective
Nat Rev Cancer
Global cancer statistics, 2012
CA Cancer J Clin
Hereditary ovarian cancer: not only BRCA 1 and 2 genes
Biomed Res Int
Two decades after BRCA: setting paradigms in personalized cancer care and prevention
Science
Hereditary breast and ovarian cancer: new genes in confined pathways
Nat Rev Cancer
Meta-analysis of BRCA1 and BRCA2 penetrance
J Clin Oncol
Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE
J Natl Cancer Inst
Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age
Breast Cancer Res Treat
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer
J Clin Oncol
Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2
J Clin Oncol
The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population
Hum Mol Genet
Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer
J Clin Oncol
BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients
Br J Cancer
Germline BRCA1 mutations increase prostate cancer risk
Br J Cancer
BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma
J Clin Oncol
Cancer incidence in BRCA1 mutation carriers
J Natl Cancer Inst
Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer
Int J Cancer
Evaluation of the contribution of the three breast cancer susceptibility genes CHEK2, STK11, and PALB2 in non-BRCA1/2 French Canadian families with high risk of breast cancer
Genet Test Mol Biomark
Increased risk for other cancers in addition to breast cancer for CHEK2*1100delC heterozygotes estimated from the copenhagen general population study
J Clin Oncol
Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation
J Clin Oncol
CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer
J Clin Oncol
Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers
J Clin Oncol
CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls
J Clin Oncol
Breast-cancer risk in families with mutations in PALB2
N Engl J Med
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene
Science
Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States
Breast Cancer Res Treat
A recurrent mutation in PALB2 in Finnish cancer families
Nature
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing
Proc Natl Acad Sci U S A
Genetic testing for RAD51C mutations: in the clinic and community
Clin Genet
Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population
J Clin Oncol
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2022, BloodCitation Excerpt :In addition, we identified novel genes that have roles in DNA repair, including ARID1B76 and SAMHB1.77 In general for pan-cancer, defects in DNA repair genes have long been recognized as the most commonly involved genetic event in hereditary cancers78-80 including HM.74,81 Therapeutic strategies to target DNA repair pathways have been actively explored as anticancer treatment, such as PARP inhibitor and compounds targeting transducers or effectors in DNA repair pathways.82
Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response
2021, Progress in Biophysics and Molecular BiologyCitation Excerpt :It is not our intent to provide a comprehensive discussion of the different DNA repair mechanisms, but instead, we have provided Table 1 to summarize the major repair pathways, DNA substrates, and protein participants, and direct the reader to reviews for further information (Soll et al. 2017; Fedeles et al., 2015; Modrich 2016; Krokan and Bjørås 2013; Andres et al., 2015; Mullenders 2018; Scully et al., 2019; Sun et al., 2020; Chaplin and Blundell 2020). Individuals that harbor a germline defect in a key component of the DDR commonly exhibit cancer predisposition as a primary clinical phenotype (Torgovnick and Schumacher 2015; Romero-Laorden and Castro 2017). Given that DNA damage can drive mutagenic events and genomic instability, outcomes known to underlie transformation and consequent carcinogenesis, the association between ineffective DNA repair and cancer development is obvious.
Transcriptional Regulation at DSBs: Mechanisms and Consequences
2020, Trends in GeneticsCitation Excerpt :If these lesions are not faithfully repaired, they could lead to the accumulation of mutations and genomic instabilities that could drive carcinogenesis. In agreement with this, DNA repair proteins are frequently mutated in human tumors [1,2]. To cope with the massive amount of endogenous and exogenous DNA lesions (see Glossary), cells have evolved entangled but highly orchestrated DNA damage response (DDR) networks [3].