ATM mutations in Finnish breast cancer patients

Allinen, Minna; Launonen, Virpi; Laake, Kirsten; Jansen, Laila; Huusko, Pia; Kääriäinen, Helena; Børresen‐Dale, Anne‐Lise; Winqvist, Robert

doi:10.1136/jmg.39.3.192

Cited by 15 publications

(16 citation statements)

References 94 publications

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“…Taking together the results of the current and our previous study, 9 we have analyzed the entire ATM protein-encoding region in patients from 121 breast and breast-ovarian cancer families. The mutations associated with increased breast cancer susceptibility, and which were not observed among healthy controls, seemed to be restricted to those reported previously in Finnish A-T patients.…”

Section: Resultsmentioning

confidence: 99%

“…7 We have previously analyzed cases of 162 families displaying signs of hereditary susceptibility to breast cancer for the occurrence of ATM germline mutations originally identified in Finnish A-T families. 8,9 Of 8 different A-T-related mutations, only 6903insA (leading to stop at codon 2372) and 7570G?C (Ala2524Pro) were associated with increased breast cancer risk. However, the overall frequency of these 2 mutations was low, as 6903insA was observed no more than in 1 and 7570G?C in 2 families.…”

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confidence: 99%

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Association of common ATM polymorphism with bilateral breast cancer

Heikkinen

Rapakko

Karppinen

et al. 2005

Intl Journal of Cancer

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The ATM kinase has an essential role in maintaining genomic integrity. Loss of both ATM alleles results in ataxia-telangiectasia (A-T), a rare autosomal recessive neuroimmunologic disorder associated with cancer susceptibility. Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for malignancy, in particular, female breast cancer. In the current study, a full mutation analysis of the ATM gene was carried out in patients from 121 breast or breast-ovarian cancer families. We discovered that the combination of 5557G?A in cis position with IVS38-8 T?C was associated with bilateral breast cancer (OR ¼ 10.2; 95% CI ¼ 3.1-33.8; p ¼ 0.001). As the 5557G?A change has been reported to affect an exonic splicing enhancer, we hypothesized that the observed composite allele could have some effect on the correct splicing of exon 39. However, no aberrant transcripts were detected, but ATM expression levels of lymphoblast cell lines from heterozygous carriers of this combination allele were lower than from noncarriers (p ¼ 0.09). Lowered gene expression levels may have direct influence on the activities in DNA damage recognition and response pathways, as well as other genome integrity maintenance functions. Based on the results, we propose a cancer risk-modifying effect for the ATM 5557G?A, IVS38-8T?C composite allele. ' 2005 Wiley-Liss, Inc.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Association of common ATM polymorphism with bilateral breast cancer

Heikkinen

Rapakko

Karppinen

et al. 2005

Intl Journal of Cancer

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“…Furthermore, two studies on sporadic breast cancer (Vorechovsky et al, 1996;Bebb et al, 1999) reported the absence of ATM mutations in sporadic breast cancer patients, whereas Broeks et al (2000) found seven ATM mutations among 82 unselected breast cancer cases. In a recent study by Allinen et al (2002), we investigated the possible occurrence of the germline mutations seen in Finnish ataxiatelangiectasia patients in both hereditary and sporadic breast cancers, and observed ATM alterations in only a small fraction of the hereditary cases, but not in the sporadic ones, which included the cohort displaying LOH in 11q investigated here.…”

Section: Introductionmentioning

confidence: 94%

Analysis of 11q21–24 loss of heterozygosity candidate target genes in breast cancer: Indications of TSLC1 promoter hypermethylation

Allinen

Peri

Kujala

et al. 2002

Genes Chromosomes & Cancer

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Loss of heterozygosity (LOH) at the distal half of chromosome arm 11q is frequent in a variety of human tumors, including breast cancer, and is often associated with poor prognosis. In an ongoing attempt to locate and characterize the main target genes within this chromosome region, we first looked for aberrations in known genes either suggested to be involved in tumorigenesis or shown to suppress tumor formation. We examined 31 primary breast tumors showing LOH in 11q21-24 for mutations in the MRE11A, CHK1, PPP2R1B, and TSLC1 genes. The absence of intragenic alterations related to cancer led us next to evaluate possible gene silencing resulting from promoter region CpG hypermethylation, using the bisulfite sequencing technique. In addition to the four genes mentioned above, we also analyzed the ATM gene, which had been investigated for certain germline mutations in an earlier study. Only the TSLC1 promoter region exhibited aberrant methylation patterns, and altogether 33% (10/30) of the successfully analyzed tumors showed evidence of elevated levels of TSLC1 CpG methylation. Ten percent (3/30) of the tumors showed significantly increased methylation. Thus, as has been shown in lung and some other forms of cancer, hypermethylation of the TSLC1 promoter region is also frequently a second hit along with LOH in breast cancer.

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“…14 Two recurrent ATM mutations originally identified in Ataxia-telangiectasia families have been detected also in BC patients: c.6908dupA (previously marked as 6903insA) in 0.4% of unselected and in 0.6% of familial patients, and a pathogenic missense c.7570G>C in 0.2% of both unselected and familial patients. 25,26 Finally, two mutations in RAD51C, c.93delG and c.837+1G>A, and one in RAD51D, c.576+1G>A, were each observed in about 0.5% of unselected OC patients. 27,28 Besides these, a likely pathogenic RAD51C ex1-7 duplication was recently identified in 0.4% of unselected OC patients.…”

Section: Introductionmentioning

confidence: 99%

“…Of these, c.5101C>T is the most common with a frequency of 2.8% in unselected patients, 3.1% in BC families and 5.6% in patients with triple‐negative BC . Two recurrent ATM mutations originally identified in Ataxia‐telangiectasia families have been detected also in BC patients: c.6908dupA (previously marked as 6903insA) in 0.4% of unselected and in 0.6% of familial patients, and a pathogenic missense c.7570G>C in 0.2% of both unselected and familial patients . Finally, two mutations in RAD51C , c.93delG and c.837+1G>A, and one in RAD51D , c.576+1G>A, were each observed in about 0.5% of unselected OC patients .…”

Section: Introductionmentioning

confidence: 99%

Recurrent moderate‐risk mutations in Finnish breast and ovarian cancer patients

Nurmi

Muranen

Pelttari

et al. 2019

Intl Journal of Cancer

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Mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in PALB2, CHEK2, ATM, FANCM, RAD51C and RAD51D genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being CHEK2 c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of CHEK2 c.319+2T>A and c.444+1G>A in Finnish BC patients. CHEK2 c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58–18.45], p = 0.007) and similarly in the familial patient group. CHEK2 c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate‐risk gene mutations in 2,487 BC patients, 556 OC patients and 261 BRCA1/2 carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 BRCA1/2‐negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate‐risk gene mutation was found in 12.5% of BRCA1 families and 7.1% of BRCA1 index patients, as well as in 17.0% of BRCA2 families and 11.3% of BRCA2 index patients, and the mutations were associated with an additional risk in the BRCA1/2 index patients (OR = 2.63 [1.15–5.48], p = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.

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ATM mutations in Finnish breast cancer patients

Cited by 15 publications

References 94 publications

Association of common ATM polymorphism with bilateral breast cancer

Association of common ATM polymorphism with bilateral breast cancer

Analysis of 11q21–24 loss of heterozygosity candidate target genes in breast cancer: Indications of TSLC1 promoter hypermethylation

Recurrent moderate‐risk mutations in Finnish breast and ovarian cancer patients

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