Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia

Abstract

Epidemiological studies have consistently shown elevated rates of breast cancer among female blood relatives of patients with ataxia telangiectasia (AT), a rare autosomal recessive disease. A large proportion of the members of AT families are carriers of AT-causing gene mutations in ATM (Ataxia Telangiectasia Mutated), and it has been hypothesised that these otherwise healthy carriers are predisposed to breast cancer. This is an extended and enlarged follow-up study of cancer incidence in blood relatives of 75 patients with verified AT in 66 Nordic families. Blood relatives were identified through population registry linkages, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. The ATM mutation carrier probabilities of relatives were assigned from the combined information on location in family, consanguinity, if any, and supplementary carrier screening in some families. Among the 1445 blood relatives of AT patients, 225 cancers were observed, with 170.4 expected, yielding a standardised incidence ratio (SIR) of 1.3 (95% confidence interval (CI), 1.1 -1.4). Invasive breast cancer occurred in 34 female relatives (SIR, 1.7; 95% CI, 1.2 -2.4) and was diagnosed in 21 women before the age of 55 years (SIR, 2.9; 95% CI, 1.8 -4.5), including seven mothers of probands (SIR, 8.1; 95% CI,. When the group of mothers was excluded, no clear relationship was observed between the allocated mutation carrier probability of each family member and the extent of breast cancer risk. We concluded that the increased risk for female breast cancer seen in 66 Nordic AT families appeared to be restricted to women under the age of 55 years and was due mainly to a very high risk in the group of mothers. The findings of breast cancer risk in mothers, but not other likely mutation carriers, in this and other studies raises questions about the hypothesis of a simple causal relationship with ATM heterozygosity.

Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling

“…This finding has been confirmed in other studies of A-T families (Athma et al, 1996;Inskip et al, 1999;Janin et al, 1999;Geoffroy-Perez et al, 2001;Olsen et al, 2001Olsen et al, , 2005Thompson et al, 2005b). The overall relative risk of breast cancer in A-T heterozygotes is estimated to be 2.23 (95% CI ¼ 1.16-4.28) compared with the general population, and 4.94 (95% CI ¼ 1.90-12.9) in those younger than age 50 years (Thompson et al, 2005b).…”

ATM and breast cancer susceptibility

“…However, there are indications that factors such as age and the specific mutation may influence breast cancer risk. Epidemiological analyses suggest that the risk of breast cancer in ATM carriers is higher in women under 50 years and may be higher in first-degree relatives of ataxia-telangiectasia cases compared to more distantly related ATM heterozygotes (Olson et al, 2005;Thompson et al, 2005b). The breast cancer risk in individuals above and below 50 years was not significantly different in the study by Renwick et al (2006) but there was limited power to investigate the age-specific risks of ATM mutations.…”

ATM haplotypes and breast cancer risk in Jewish high-risk women

“…Epidemiological studies have consistently shown that female relatives of A-T patients are at an increased risk for developing breast cancer (reviewed in Hall, 2005). Interestingly, this increased risk was predominantly observed in the mothers of A-T carriers and not in siblings and offsprings (Olsen et al, 2005). Yet, not all studies confirmed the associated breast cancer risk conferred by being an ATM heterozygous mutation carrier (Vorechovsky et al, 1996;FitzGerald et al, 1997;Bay et al, 1998;Chen et al, 1998).…”