Functional Analysis of Missense Variants in the Putative Breast Cancer Susceptibility Gene<i>XRCC2</i>

Hilbers, Florentine; Luijsterburg, Martijn S.; Wiegant, Wouter W.; Meijers, Caro M.; Völker-Albert, Moritz; Boonen, Rick A.C.M.; Asperen, Christi J. van; Devilee, Peter; Attikum, Haico van

doi:10.1002/humu.23019

Cited by 12 publications

(9 citation statements)

References 47 publications

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“…It also forms a heterodimer complex with other members of the RAD51 protein family such as RAD51B, RAD51C, RAD51D, XRCC3, BRCA1, and BRCA2. This heterodimer is needed for the localization of RAD51, which plays a key role in mediating HRR at DSB sites [ 30 , 31 ]. It is postulated that disruption of DSB repair contributes to carcinogenesis through the accumulation of genetic errors and genetic instability [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of sporadic breast cancer in Sri Lankan women

et al. 2018

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BackgroundWhile a range of common genetic variants have been identified to be associated with risk of sporadic breast cancer in several Western studies, little is known about their role in South Asian populations. Our objective was to examine the association between common genetic variants in breast cancer related genes and risk of breast cancer in a cohort of Sri Lankan women.MethodsA case-control study of 350 postmenopausal women with breast cancer and 350 healthy postmenopausal women was conducted. Genotyping using the iPLEX GOLD assay was done for 56 haplotype-tagging single nucleotide polymorphisms (SNPs) in 36 breast cancer related genes. Testing for association was done using an additive genetic model. Odds ratios and 95% confidence intervals were calculated using adjusted logistic regression models.ResultsFour SNPs [rs3218550 (XRCC2), rs6917 (PHB), rs1801516 (ATM), and rs13689 (CDH1)] were significantly associated with risk of breast cancer. The rs3218550 T allele and rs6917 A allele increased breast cancer risk by 1.5-fold and 1.4-fold, respectively. The CTC haplotype defined by the SNPs rs3218552|rs3218550|rs3218536 on chromosome 7 (P = 0.0088) and the CA haplotype defined by the SNPs rs1049620|rs6917 on chromosome 17 (P = 0.0067) were significantly associated with increased risk of breast cancer. The rs1801516 A allele and the rs13689 C allele decreased breast cancer risk by 0.6-fold and 0.7-fold, respectively.ConclusionsThese findings suggest that common genetic polymorphisms in the XRCC2, PHB, CDH1 and ATM genes are associated with risk of breast cancer among Sri Lankan postmenopausal women. The exact biological mechanisms of how these variants regulate overall breast cancer risk need further evaluation using functional studies.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4112-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Genetic determinants of sporadic breast cancer in Sri Lankan women

et al. 2018

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“…XRCC2 overexpression has also been identified as a marker for radioresistance, with knockdown causing enhanced sensitivity [135]. Mutation was initially associated with breast cancer development [136], however this has recently been disputed, and remains controversial [137,138]. Knockdown of XRCC2 is also known to cause sensitivity to PARP inhibitors [139].…”

Section: Homologous Recombination Fa Proteinsmentioning

confidence: 99%

Inhibitors of the Fanconi anaemia pathway as potential antitumour agents for ovarian cancer

Taylor

Arends

Langdon

2020

Exploration of Targeted Anti-Tumor Therapy

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The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach.

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“…In the largest study to date, of 13,087 breast cancer and 5,488 control cases from the UK, a total of 11 truncating and 32 rare missense variants were found (Decker et al, 2017). A recent study functionally characterized breast cancer-associated variants and found that each of the truncating or frameshift variants displayed compromised activity, while most of the missense variants tested displayed a minor change or no change in activity (Hilbers et al, 2016). Notably, a bi-allelic germ-line nonsense mutation in XRCC2 c.643C>T encoding p.R215X is causative for the U complementation group of Fanconi anemia, FA-U (Park et al, 2016; Shamseldin et al, 2012).…”

Section: Mutationsmentioning

confidence: 99%

“…However, no other study so far has confirmed mutation of XRCC2 as a significant cause of inherited breast cancer (Hilbers et al, 2016; Hilbers et al, 2012; Pelttari et al, 2015). For example, Hilbers et al analysed the coding region of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls (Hilbers et al, 2012).…”

Section: Implicated Inmentioning

confidence: 99%

XRCC2 (X-ray repair cross complementing 2)

Andreassen

2019

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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XRCC2 is one of five somatic RAD51 paralogs, all of which have Walker A and B ATPase motifs. Each of the paralogs, including XRCC2, has a function in DNA double-strand break repair by homologous recombination (HR). However, their individual roles are not as well understood as that of RAD51 itself. The XRCC2 protein forms a complex (BCDX2) with three other RAD51 paralogs, RAD51B, RAD51C and RAD51D. It is believed that the BCDX2 complex mediates HR downstream of BRCA2 but upstream of RAD51, as XRCC2 is involved in the assembly of RAD51 into DNA damage foci. XRCC2 can bind DNA and, along with RAD51D, can promote homologous pairing in vitro. Consistent with its role in HR, XRCC2-deficient cells have increased levels of spontaneous chromosome instability, and exhibit hypersensitivity to DNA interstrand crosslinking agents such as mitomycin C and cisplatin as well as ionizing radiation, alkylating agents and aldehydes. XRCC2 also functions in promoting DNA replication and chromosome segregation. Biallelic mutation of XRCC2 (FANCU) causes the FA-U subtype of FA, while heterozygosity for deleterious mutations in XRCC2 may be associated with an increased breast cancer risk. XRCC2 appears to function ‘downstream’ in the FA pathway, since it is not required for FANCD2 monoubiquitination, which is the central step in the FA pathway. Clinically, the only known FA-U patient in the world exhibits severe congenital abnormalities, but had not developed, by seven years of age, the bone marrow failure and cancer that are often seen in patients from other FA complementation groups.

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Functional Analysis of Missense Variants in the Putative Breast Cancer Susceptibility GeneXRCC2

Cited by 12 publications

References 47 publications

Genetic determinants of sporadic breast cancer in Sri Lankan women

Genetic determinants of sporadic breast cancer in Sri Lankan women

Inhibitors of the Fanconi anaemia pathway as potential antitumour agents for ovarian cancer

XRCC2 (X-ray repair cross complementing 2)

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