Inherited variants in XRCC2 and the risk of breast cancer

Abstract

BackgroundXRCC2 participates in homologous recombination and in DNA repair. XRCC2 has been reported to be a breast cancer susceptibility gene and is now included in several breast cancer susceptibility gene panels.MethodsWe sequenced XRCC2 in 617 Polish women with familial breast cancer and found a founder mutation. We then genotyped 12,617 women with breast cancer and 4599 controls for the XRCC2 founder mutation.ResultsWe identified a recurrent truncating mutation of XRCC2 (c.96delT, p.Phe32fs) in 3 of 617 patients with familial breast cancer who were sequenced. The c.96delT mutation was then detected in 29 of 12,617 unselected breast cancer cases (0.23%) compared to 11 of 4599 cancer-free women (0.24%) (OR = 0.96; 95% CI 0.48–1.93). The mutation frequency in 1988 women with familial breast cancer was 0.2% (OR = 0.84, 95% CI 0.27–2.65). Breast cancers in XRCC2 mutation carriers and non-carriers were similar with respect to age of diagnosis and clinical characteristics. Loss of the wild-type XRCC2 allele was observed only in one of the eight breast cancers from patients who carried the XRCC2 mutation. No cancer type was more common in first- or second-degree relatives of XRCC2 mutation carriers than in relatives of the non-carriers.ConclusionXRCC2 c.96delT is a protein-truncating founder variant in Poland. There is no evidence that this mutation predisposes to breast cancer (and other cancers). It is premature to consider XRCC2 as a breast cancer-predisposing gene.

Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence

“…Mutations in TP53 , CDH1 , PTEN , and STK11 are also associated with breast cancer and TNBC incidence ( Corso et al, 2018 ; Shahbandi et al, 2020 ). Mutations in the XRCC2 gene are also associated with high risk of breast cancer ( Kluźniak et al, 2019 ). Further, it has been revealed that BRCA1 -related tumors profile resembles the TNBC subtype, while the profile of the BRCA2-associated tumor correlates to luminal-like breast cancers, particularly the Luminal B subtype ( Incorvaia et al, 2020 ).…”

Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications

“…Like RA51B , XRCC2 and XRCC3 germline PVs are uncommon and have uncertain clinical significance. An XRCC2 founder variant (c.96delT) reported among Polish patients with breast cancer did not affect breast cancer risks (OR, 0.8; 95% CI, 0.3–2.7) [85]. Another study of 13,087 patients with breast cancer also failed to find any statistically significant risk estimates for XRCC2 germline PVs (OR, 0.9; 95% CI, 0.3–4.2) [86].…”

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

“…However, the role of monoallelic mutations in the remaining FA genes regarding cancer predisposition is a matter of discussion. Over the last few years, several case-controls studies have indicated that monoallelic FANCM [7][8][9][10][11][12][13][14][15] truncating mutations are breast cancer risk factors; in addition, there are inconsistent results regarding FANCA [16][17][18][19], FANCC [20][21][22][23][24], SLX4 [25][26][27] and XRCC2 [28][29][30].…”