Incidence of Cancer in 161 Families Affected by Ataxia–Telangiectasia

Swift, Michael; Morrell, Daphne; Massey, Ruby B.; Chase, Charles L.

doi:10.1056/nejm199112263252602

Cited by 871 publications

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“…there is exvidence that AT heterozvgositv may be associated with an increased frequency of certain types of cancer. particularly breast carcinoma (Swift et al 1987. 1991: Pippard et al 1988.…”

Section: Discussionmentioning

confidence: 99%

Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients

Shayeghi

Seal²,

Regan³

et al. 1998

Br J Cancer

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Summary Of patients being treated by radiotherapy for cancer, a small proportion develop marked long-term radiation damage. It is believed that this is due. at least in part, to intrinsic individual differences in radiosensitivity, but the underlying mechanism is unknown. Individuals affected by the recessive disease ataxia telangiectasia (AT) exhibit extreme sensitivity to ionizing radiation. Cells from such individuals are also radiosensitive in in vitro assays, and cells from AT heterozygotes are reported to show in vitro radiosensitivity at an intermediate level between homozygotes and control subjects. In order to examine the possibility that a defect in the ATM gene may account for a proportion of radiotherapy complications, 41 breast cancer patients developing marked changes in breast appearance after radiotherapy and 39 control subjects who showed no clinicalty detectable reaction after radiotherapy were screened for mutations in the ATM gene. One out of 41 cases showing adverse reactions was heterozygous for a mutation (insertion A at NT 898) that is predicted to generate a truncated protein of 251 amino acids. No truncating mutations were detected in the control subjects. On the basis of this result, the estimated percentage (950o confidence interval) of AT heterozygous patients in radiosensitive cases was 2.4% (0.1-12.9%) and in control subjects (0-9.0%). We conclude that ATM gene defects are not the major cause of radiotherapy complications in women with breast cancer.

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Section: Discussionmentioning

confidence: 99%

Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients

Shayeghi

Seal²,

Regan³

et al. 1998

Br J Cancer

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Section: Introductionmentioning

confidence: 99%

“…Within this fraction of breast cancer the germline mutations in BRCA1 (Miki et al, 1994) and BRCA2 genes most frequently form a favorable genetic background for the disease. Also at increased risk are the carriers of one abnormal allele of the ataxia telangiectasia gene (Swift et al, 1991), the carriers of rare minisatelite allele at the HRAS1 locus (Krontiris et al, 1993) and the members of Li Fraumeni families with germline mutation in the p53 gene (Srivastava et al, 1990).The BRCA1 gene located on chromosome 17q21 (Hall et al, 1990) is also linked to hereditary ovarian cancer (Narod et al, 1991). More than 400 BRCA1 sequence variants have been identi®ed thus far and deposited in Breast Cancer Information Core Database (Friend et al, 1995) which now contains about 150 di erent cancer predisposing mutations.…”

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confidence: 99%

Novel BRCA1 mutations and more frequent intron-20 alteration found among 236 women from Western Poland

et al. 1997

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Three di erent novel BRCA1 mutations, ®ve independent cases of the same 12 bp insertion-duplication in intron-20 and two novel rare BRCA1 sequence variants were identi®ed among 122 Polish women with positive, in most cases moderate family history of breast and/or ovarian cancer, 80 controls and 34 unselected breast cancer tissue specimens. All mutations and variants were germline. The 4153 delA frameshift mutation, the Tyr105Cys missense mutation and two cases of the alteration in intron-20 were found in the group of healthy women with positive family history. Two other cases of the intronic insertion were found in unselected controls. Their carriers had no family history of breast or ovarian cancer but other cancers occurred in their families. The 1782 Trp/STOP nonsense mutation and one case of the insertion in intron-20 were ®rst found in tissue specimens of breast cancer patient and breast/ovarian cancer patient, respectively. Their carriers also had no family history of breast or ovarian cancer. The distribution of the insertion in intron-20 in analysed groups and results of RT ± PCR experiments suggest a less prominent role for this variant considered earlier a splicing mutation. This study shows also, that more population-oriented research is needed, involving women with less profound or even no family history of breast and ovarian cancer, to better understand the role and signi®cance of di erent BRCA1 variants and mutations.Keywords: BRCA1; mutations and variants; SSCPheteroduplex analysis; Polish women; positive family history IntroductionApproximately one in ten women in western countries will develop breast cancer during their lifetime . In most cases the disease is sporadic; however, some 5 ± 10% of women with breast cancer inherit increased susceptibility to the disease (Claus et al., 1991). Within this fraction of breast cancer the germline mutations in BRCA1 (Miki et al., 1994) and BRCA2 genes most frequently form a favorable genetic background for the disease. Also at increased risk are the carriers of one abnormal allele of the ataxia telangiectasia gene (Swift et al., 1991), the carriers of rare minisatelite allele at the HRAS1 locus (Krontiris et al., 1993) and the members of Li Fraumeni families with germline mutation in the p53 gene (Srivastava et al., 1990).The BRCA1 gene located on chromosome 17q21 (Hall et al., 1990) is also linked to hereditary ovarian cancer (Narod et al., 1991). More than 400 BRCA1 sequence variants have been identi®ed thus far and deposited in Breast Cancer Information Core Database (Friend et al., 1995) which now contains about 150 di erent cancer predisposing mutations. Most of this knowledge comes from studies of breast and breastovarian cancer families. Therefore the known mutations are probably biased towards those with more severe e ects on phenotype. It is expected that less expressive mutations will be identi®ed when studies expand and include women with less profound family history and women from the general population. It is also very likely that the inciden...

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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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Incidence of Cancer in 161 Families Affected by Ataxia–Telangiectasia

Cited by 871 publications

References 20 publications

Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients

Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients

Novel BRCA1 mutations and more frequent intron-20 alteration found among 236 women from Western Poland

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

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