Population-based estimates of breast cancer risks associated withATMgene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry

Abstract

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

The CHEK2 gene and inherited breast cancer susceptibility

“…The 1100delC carrier status was also associated with exposure to diagnostic ionizing radiation (excluding mammography) in a populationbased study of 2311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries. The association was strongest among Caucasian women aged >45 years who were exposed >15 years before breast cancer diagnosis (OR, 4.28; 95% CI, 1.50-12.20) (Bernstein et al, 2006). The suggested association between ionizing radiation and breast cancer risk substantiates CHEK2 gene's role as a checkpoint gene for IR-induced DNA damage.…”

“…Highest population frequencies have been found in the Netherlands (1.3-1.6%) and in Finland Kleibl et al, 2005), Italy (0.11%, Caligo et al, 2004), USA (0.3-0.4%, Offit et al, 2003;Friedrichsen et al, 2004) and Canada (0.2%, Bernstein et al, 2006); the variant has not been detected in the Spanish population (Osorio et al, 2004).…”

The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience

“…Literature cites a 28-50% lifetime risk for breast cancer in ATM heterozygote mutation carriers, with an additional increased risk if a first-degree relative is affected with breast cancer. [12][13][14] Using high-risk breast cancer screening and management guidelines, we recommended breast magnetic resonance imaging and ultrasounds and discussed the availability of prophylactic surgical interventions. Although current literature is conflicting, given that ATM carriers may have an increased sensitivity to radiation, we recommended that mammography and X-rays should only be considered if no alternative method could be considered for a particular therapy, treatment, or management option.…”

Ataxia–Telangiectasia Gene (ATM) Mutation Heterozygosity in Breast Cancer: A Narrative Review

“…Most variants that cause the at syndrome result in truncation of its protein product 27 , but at least 170 missense variants have been identified 28 . In a meta-analysis, no difference in the pooled frequency of ATM missense variants were evident in cases compared with controls 28 , but the V2424G variant is still thought to be pathogenic [29][30][31][32] . In fact, some literature suggests that the V2424G missense variant portends a particularly high risk of breast cancer, reaching a cumulative risk of 52% (95% ci: 28% to 80%) at 70 years of age 31 .…”