PALB2,CHEK2andATMrare variants and cancer risk: data from COGS

Abstract

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk

“…These two studies [2, 3] together identified the p.Leu939Trp mutation in 10/1741 (0.57 %) women with breast cancer and 8/1534 (0.52 %) unaffected controls, suggesting that this mutation is not associated with breast cancer risk. Further, we later published a third study corroborating this null finding [4] and have subsequently reported additional evidence that the p.Leu939Trp mutation is not associated with breast cancer risk, based on genotyping of 42,671 breast cancer cases and 42,164 controls (odds ratio = 1.05, 95 % confidence interval = 0.83–1.32, p value = 0.70) [5]. Finally, we observed that the p.Leu939Trp mutation does not disrupt the HR-mediated DNA repair activity of PALB2 (Fig.…”

Association of Common Genetic Variants With Contralateral Breast Cancer Risk in the WECARE Study

“…The risk is particularly high in women with rare high-penetrance sequence variants, such as mutations in BRCA1 or BRCA2, where the 10-year risk may approach 25% to 30% (4,5). Mutations in CHEK2 also increase the risk of CBC, albeit to a lesser degree (6,7), and rare pathogenic PALB2 mutations have also been shown to increase the risk of CBC (8,9). In some family studies and within subgroups of breast cancer patients, rare mutations in the ATM gene have also been shown to increase the risk of CBC (10,11).…”

A Whole Exome Study Identifies Novel Candidate Genes for Vertebral Bone Marrow Signal Changes (Modic Changes)

“…mutations descending from a single ancestor have been described for example in genes causing familial breast cancer. [47][48][49][50][51] Chondrocytic cell lines were not available for the predictions of the promoter and enhancer regions. Instead data from HSMM and GM12878 cell lines were used.…”