Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer

Athma, Prasanna; Rappaport, Rebecca; Swift, Michael

doi:10.1016/s0165-4608(96)00328-7

Cited by 300 publications

(180 citation statements)

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“…Most of the epidemiological studies of AT relatives report an increased risk of breast cancer at younger ages, below 45-55 years (Inskip et al, 1999;Janin et al, 1999;Olsen et al, 2000), contrary from Athma et al (1996). In the present study, only 150 of the patients analysed were below the age of 55 at time of diagnosis, which may explain the low frequency of mutations seen.…”

Section: Discussioncontrasting

confidence: 62%

“…Heterozygotes are clinically asymptomatic, but a number of epidemiological studies in AT families have noted a significant increase in cancer incidence, in breast cancer particularly (Easton, 1994;Athma et al, 1996;Inskip et al, 1999;Janin et al, 1999;Olsen et al, 2000). The relative risk was in the range 1.5-9, depending on population, age and family relation.…”

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confidence: 99%

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Screening breast cancer patients for Norwegian ATM mutations

Laake

Andersen

et al. 2000

Br J Cancer

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483 Norwegian breast cancer patients were screened for six different ataxia telangiectasia mutated ( ATM ) mutations previously found to account for 83% of the disease alleles in Norwegian ataxia telangiectasia (AT) patients. Only one carrier was found. These results provide no evidence in favour of an excess risk of breast cancer associated with heterozygosity for classical AT mutations, but remain consistent with a maximum 2.4-fold increased risk. © 2000 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussioncontrasting

confidence: 62%

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confidence: 99%

Screening breast cancer patients for Norwegian ATM mutations

Laake

Andersen

et al. 2000

Br J Cancer

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“…Patients exhibit a progressive cerebellar ataxia, in addition to severe immune de®ciencies, gonadal atrophy, telangiectases, increased risk for cancer, particularly lymphomas, and radiation sensitivity. Additionally, carriers are suspected to be prone to other cancers including breast cancer (Athma et al, 1996;Chen et al, 1998;Stankovic et al, 1999;Swift et al, 1990;Yuille and Coignet, 1998).…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of Xenopus ATM (X-ATM): expression, localization, and complex formation during oogenesis and early development

1999

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ATM, the gene product mutated in Ataxia Telangiectasia (A-T) encodes a 350-kDa protein involved in the regulation of several cellular responses to DNA breaks. We used a degenerate PCR-based strategy to isolate a partial clone of X-ATM, the Xenopus homologue of human ATM. Sequence analysis and con®rmed that the clone was most closely related to human ATM. Xenopus ATM protein (X-ATM) is 85% identical to human ATM within the kinase domain and 71% identical over the carboxyl-terminal half of the protein. Polyclonal antibodies raised against recombinant X-ATM are highly speci®c for the ATM protein and recognize a single polypeptide of 370-kDa in oocytes, embryos, egg extracts and a Xenopus cell line. We found that X-ATM was expressed maternally in eggs and as early as stage II pre-vitellogenic oocytes, and the protein and mRNA were present at relatively constant levels throughout development. Subcellular fractionation showed that the protein was nuclear in both the female and male germlines. The level of X-ATM protein did not change throughout the meiotic divisions or the synchronous mitotic cycles of cleavage stage embryos. In addition, we did not observe any change in the level or mobility of X-ATM protein following g-irradiation of embryos. Finally, we also demonstrated that X-ATM was present in a high molecular weight complex of approximately 500 kDa containing the X-ATM protein and other, as yet unidenti®ed component(s).

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“…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.…”

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confidence: 99%

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

Bernstein

Thompson

et al. 2003

Br J Cancer

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Recent reports suggest that two ATM gene mutations, 7271T4G and IVS10-6T4G, are associated with a high risk of breast cancer among multiple-case families. To assess the importance of these two mutations in another 'high-risk' group, young women (under age 51) with multiple primaries, we screened a large population-based series of young women with bilateral breast cancer and compared the frequency of these mutations among similar women diagnosed with unilateral breast cancer. The 1149 women included were enrolled in an ongoing population-based case -control study of the genetic factors that contribute to bilateral breast cancer; they were not selected on the basis of family history of cancer. Screening for 7271T4G and IVS10-6T4G ATM gene mutations was conducted using DHPLC followed by direct sequencing. The 7271T4G mutation was detected in one out of 638 (0.2%) women with unilateral breast cancer and in none of the bilateral cases, and the IVS10-6T4G mutation in one out of 511 (0.2%) bilateral and in eight out of 638 (1.3%) unilateral breast cancer cases. Carriers of either mutation were not limited to women with a family history. Given the likelihood that young women with bilateral breast cancer have a genetic predisposition, the observed mutation distribution is contrary to that expected if these two mutations were to play an important role in breast carcinogenesis among individuals at high risk. Keywords: ATM gene screening; 7271T4G mutation; IVS10-6T4G mutation; breast cancer; bilateral breast cancer ATM (for ataxia-telangiectasia (A-T) mutated), a gene whose product plays a critical role in signalling and responding to the presence of DNA double-strand breaks, is mutated in the autosomal recessive disorder A-T. The incidence of breast cancer among heterozygous carriers in A-T families, along with the known biochemical interactions between the products of the ATM and BRCA1 genes, has suggested a role for ATM in breast cancer risk. The recent study by Chenevix-Trench et al (2002) reported a greatly elevated risk of breast cancer among five members from multiple-case breast cancer families, who were heterozygous for ATM gene mutations, 7271T4G or IVS10-6T4G. The estimated combined penetrance of the two mutations was 60% (32 -90%) to age 70 years. This is equivalent to a relative risk (RR) of 15.7 (95% confidence interval (CI) ¼ 6.4 -38.0) compared to the general population. 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, 95% CI 3.7 -45.8) (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 ...

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Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer

Cited by 300 publications

References 14 publications

Screening breast cancer patients for Norwegian ATM mutations

Screening breast cancer patients for Norwegian ATM mutations

Isolation and characterization of Xenopus ATM (X-ATM): expression, localization, and complex formation during oogenesis and early development

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

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