Breast and Other Cancers in Families with Ataxia-Telangiectasia

Abstract

Patients who are homozygous for ataxia-telangiectasia have an exceptionally high incidence of cancer. In a group of families expected to have a high proportion of heterozygotes for ataxia-telangiectasia, we tested the hypothesis that such heterozygotes, estimated to make up 0.68 to 7.7 percent of the U.S. white population, also have an excess cancer risk. Retrospective cancer incidence rates in adult blood relatives of patients with ataxia-telangiectasia in 110 white non-Amish families were significantly elevated over the incidence rates in spouse controls (rate ratios, 1.6 for men [P = 0.032]; 2.0 for women [P = 0.013]). For persons who are heterozygous for ataxia-telangiectasia, the relative risk of cancer was estimated to be 2.3 for men (P = 0.014) and 3.1 for women (P = 0.004). Breast cancer in women was the cancer most clearly associated with heterozygosity for ataxia-telangiectasia (rate ratio, 3.0 [P = 0.028]; heterozygote relative risk, 6.8 [P = 0.006]). On the basis of this estimated relative risk of 6.8 and an estimated heterozygote frequency in the general population of 1.4 percent, 8.8 percent of patients with breast cancer in the U.S. white population would be heterozygous for ataxia-telangiectasia. We conclude that heterozygous carriers of the gene for ataxia-telangiectasia have an excess risk of cancer, particularly breast cancer in women.

Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions

“…There are several potential candidates. Since the ATM gene has been suspected to play a role in cancer susceptibility (Swift et al, 1987), its participation may be suspected. The involvement of the MLL/ALL1 gene (Rowley, 1993) located close to D11S1356 (Van Heyningen and Little, 1995) and which has been found to be deleted in a gastric carcinoma cell line (Ba a et al, 1995), or of unidenti®ed tumor suppressor genes, potentially also involved in familial cases (Lindblom et al, 1994;Sobol et al, 1994), should also be investigated.…”

“…Increased susceptibility to breast cancer has been noted in carriers of constitutional translocations involving the 11q23 band (Lindblom et al, 1994). The possible involvement of the recently isolated (Savitsky et al, 1995) ataxia-telangiectasia (ATM) gene, located at 11q22-23, in breast cancer susceptibility has been suggested (Swift et al, 1987). The importance of putative loci from chromosome region 11q22-23 in sporadic breast cancer, suspected after cytogenetic studies (Feri-Passantonopoulou et al, 1991;Hainsworth et al,, 1991), has been recently revealed by LOH analysis (Carter et al, 1994;Hampton et al, 1994a;Koreth et al, 1995;Windqvist et al, 1995).…”

ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer

“…These findings are consistent with two earlier studies: one study of the British families that first identified the 7271T4G mutation and reported a similarly large increased risk of breast cancer among three carriers of that mutation (RR ¼ 12.7,) (Stankovic et al, 1998); and a second study by Broeks (Broeks et al, 2000) of earlyonset female breast cancer, where three out of the seven ATM mutations found were IVS10-6T4G. While not all studies of ATM gene mutations demonstrate an excess risk of breast cancer (FitzGerald et al, 1997;Bebb et al, 1999;Shafman et al, 2000), studies that have screened for missense mutations (Athma et al, 1996;Teraoka et al, 2001) and those that have examined risk among family members of A-T patients (obligate heterozygotes) (Swift et al, 1987(Swift et al, , 1991Pippard et al, 1988;Borresen et al, 1990;Inskip et al, 1999;Olsen et al, 2001) have consistently found an elevated risk. Combined, these results provide evidence for an increased breast cancer risk associated with specific ATM gene mutations.…”

Design and analysis of epidemiological studies of excess cancer among children exposed to chernobyl radionuclides

“…This enables one to determine if the genetic changes seen in the 215 families represent true mutations and not rare polymorphisms or variants in the community. For loci which do not result in such a high frequency of malignancy that Mendelian inheritance is apparent, one may perform a case-control analysis where the frequency of that allele in unrelated affected individuals is compared to the frequency in appropriate control cases [54]. Several of the gene products which have been identified which predispose to cancer have been found to be components of the cellular response to DNA damage.…”

“…Exogenous factors consist of physical, chemical and biological agents. The most commonly studied physical agents are ultraviolet radiation, ionizing radiation, and extremely low frequency (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) Hz) magnetic fields. Examples of chemical exogenous factors are environmental pollutants, diethylstilbestrol, tobacco, N-nitroso compounds, aflatoxin and androgenic steroids.…”