An Allelic Variant at the<i>ATM</i>Locus Is Implicated in Breast Cancer Susceptibility

Larson, Garry P.; Zhang, Guoxiang; Ding, Shaofeng; Foldenauer, Kimberly; Udar, Nitin; Gatti, Richard A.; Neuberg, Donna; Lunetta, Kathryn L.; Ruckdeschel, John C.; Longmate, Jeffrey; Flanagan, Steven D.; Krontiris, Theodore G.

doi:10.1089/gte.1997.1.165

Cited by 40 publications

(26 citation statements)

References 12 publications

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“…There may be additional, yet undetermined, factors that influence the contralateral breast cancer risk. Some of the known putative genetic modifiers include ATM mutations, rare H-ras alleles or androgen receptor gene variations (Phelan et al, 1996;Larson et al, 1998;Rebbeck et al, 1999;Broeks et al, 2000). We have presently no evidence that bilaterality of breast cancer alone were a strong indicator of BRCA1 and BRCA2 mutations if adjusted for age and family history.…”

Section: Discussionmentioning

confidence: 73%

“…We thus investigated whether more common missense substitutions of BRCA1 or BRCA2 might play a role as predisposing factors towards contralateral cancer. Missense substitutions in other tumour suppressor genes have been described as lowpenetrance mutations that may predispose to certain malignancies or modify disease progression (Larson et al, 1998;Otterson et al, 1999;Varley et al, 1999; Lumin et al, 2000;Rebbeck et al, 2000), and a few missense variants of the BRCA1 and BRCA2 proteins, including the Gln356Arg, Arg841Trp and Leu871Pro substitutions of BRCA1 and the Asn372His substitution of BRCA2, have previously been implicated in the susceptibility to breast or ovarian cancer (Barker et al, 1996;Durocher et al, 1996;Dunning et al, 1996;Healey et al, 2000). However, none of the common BRCA1 and BRCA2 variants occurred at a significantly increased prevalence in our patients with bilateral cancer, nor did we find a deviation of the genotype distributions from Hardy-Weinberg equilibrium.…”

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confidence: 99%

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Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

et al. 2001

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Summary Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations. 850-858 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2016 of the patients. After written informed consent had been obtained, blood samples were collected from 1000 participating patients. 75 patients had developed bilateral breast cancer and took part in this study. This proportion of 7.5% of cases with bilateral disease was the same as has been previously reported in another series of over 500 German breast cancer patients (Mose et al, 1995), indicating that our cohort is representative for a hospital-based cancer population in Germany. As a comparison group for mutation frequency determination, we selected 75 patients with unilateral breast cancer from the total cohort who were pairwise matched with respect to age and family history at the time of treatment.Clinical data of the patients with bilateral breast cancer were collected and compared with data of the whole series of 1000 breast cancer patients. In 29 patients, bilateral breast cancer occurred simultaneously. In the other 46 patients, contralateral breast cancer developed with a median time interval of 7.2 years (range 1 to 40 years). A time interval of at least 3 years was observed in 37 patients. The median age at diagnosis of the first breast cancer was 54 years, compared with 57 years in the total cohort. 22 patients (29.3%) were younger than 50 years and 9 patients (12%) younger than 40 years at first diagnosis. Selfreported fam...

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Section: Discussionmentioning

confidence: 73%

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confidence: 99%

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

et al. 2001

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“…This raises the possibility that, like mutations in BRCA1 itself, changes in Chk2, ATR, or ATM activity may promote genetic instability and increase susceptibility to the development of breast cancer and other tumors. A growing body of evidence has suggested that ATM mutations confer increased susceptibility to breast cancer (91)(92)(93)(94)(95). Epidemiologic studies have put the Chk2 and BRCA1 in the same breast cancer development pathway (96,97).…”

Section: Post-transcriptional Regulation Of Brca1 By Phosphorylationmentioning

confidence: 99%

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang

Powell

2005

Molecular Cancer Research

187

154

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The tumor suppressor gene BRCA1 was cloned in 1994 based on its linkage to early-onset breast and ovarian cancer. Although the BRCA1 protein has been implicated in multiple cellular functions, the precise mechanism that determines its tumor suppressor activity is not defined. Currently, the emerging picture is that BRCA1 plays an important role in maintaining genomic integrity by protecting cells from double-strand breaks (DSB) that arise during DNA replication or after DNA damage. The DSB repair pathways available in mammalian cells are homologous recombination and nonhomologous end-joining. BRCA1 function seems to be regulated by specific phosphorylations in response to DNA damage and we will focus this review on the roles played by BRCA1 in DNA repair and cell cycle checkpoints. Finally, we will explore the idea that tumor suppression by BRCA1 depends on its control of DNA DSB repair, resulting in the promotion of error-free and the inhibition of error-prone recombinational repair.

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“…Significant evidence exists that heterozygous ATM carriers have an elevated lifetime risk of developing breast cancer (Swift et al 1987;Athma et al 1996;Larson et al 1998); however, there is disagreement about the magnitude of this effect (Easton 1994;Bishop and Hopper 1997;Fitzgerald et al 1997). This debate is especially relevant owing to the large frequency of ATM mutation carriers, estimated to comprise ∼1.4% of the general population, who could account for up to 6.5% of all breast cancer cases (Athma et al 1996).…”

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confidence: 99%

Strategies for Mutational Analysis of the Large Multiexon ATM Gene Using High-Density Oligonucleotide Arrays

Hacia¹,

Sun²,

Hunt³

et al. 1998

Genome Res.

103

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Mutational analysis of large genes with complex genomic structures plays an important role in medical genetics. Technical limitations associated with current mutation screening protocols have placed increased emphasis on the development of new technologies to simplify these procedures. High-density arrays of >90,000-oligonucleotide probes, 25 nucleotides in length, were designed to screen for all possible heterozygous germ-line mutations in the 9.17-kb coding region of the ATM gene. A strategy for rapidly developing multiexon PCR amplification protocols in DNA chip-based hybridization analysis was devised and implemented in preparing target for the 62 ATM coding exons. Improved algorithms for interpreting data from two-color experiments, where reference and test samples are cohybridized to the arrays, were developed. In a blinded study, 17 of 18 distinct heterozygous and 8 of 8 distinct homozygous sequence variants in the assayed region were detected accurately along with five false-positive calls while scanning >200 kb in 22 genomic DNA samples. Of eight heterozygous sequence changes found in more than one sample, six were detected in all cases. Five previously unreported sequence changes, not found by other mutational scanning methodologies on these same samples, were detected that led to either amino acid changes or premature truncation of the ATM protein. DNA chip-based assays should play a valuable role in high throughput sequence analysis of complex genes.

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An Allelic Variant at theATMLocus Is Implicated in Breast Cancer Susceptibility

Cited by 40 publications

References 12 publications

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Strategies for Mutational Analysis of the Large Multiexon ATM Gene Using High-Density Oligonucleotide Arrays

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