A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer

Bogdanova, Natalia; Cybulski, Cezary; Bermisheva, Marina; Datsyuk, Ihor; Yamini, Paria; Hillemanns, Peter; Antonenkova, N.; Хуснутдинова, Э. К.; Lubiński, Jan; Dörk, Thilo

doi:10.1007/s10549-008-0189-9

Cited by 42 publications

(33 citation statements)

References 24 publications

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“…The HMBCS which has also been described previously has been the subject of genetic association studies of rare susceptibility alleles [27][28][29][30][31] or common polymorphisms [24]. Byelorussian cases were 1945 female breast cancer patients who had been diagnosed during the years 1998-2008 at the Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N.…”

Section: Patientsmentioning

confidence: 98%

Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer

Landwehr

Bogdanova

Antonenkova

et al. 2011

Breast Cancer Res Treat

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SLX4 coordinates three structure-specific endonucleases in the DNA damage response. One subtype of Fanconi anaemia, FA-P, has recently been attributed to biallelic SLX4 gene mutations. To investigate whether monoallelic SLX4 gene defects play some role in the inherited component of breast cancer susceptibility, in this study we resequenced the whole SLX4 coding region and flanking untranslated sections in genomic DNA samples obtained from a total of 52 German or Byelorussian patients with familial breast cancer. Selected variants were subsequently screened by RFLP or TaqMan-based assays in an extended set of 965 German breast cancer cases and 985 healthy female controls. The resequencing study uncovered four new SLX4 missense substitutions, each of them in a single breast cancer patient. Three missense substitutions (p.V197A, p.G700R and p.R1034H) were not found in a subsequent screening of 240 additional breast cancer patients, while one missense substitution (p.R237Q) was more common and was detected in a total of 12 cases (1.3%) and seven controls (0.7%) in the Hannover breast cancer study. The rare missense substitution, p.G700R, resides in the conserved BTB domain and was in silico predicted to be pathogenic. Seven additional missense polymorphisms were correlated and formed one haplotype which was, however, neither associated with breast cancer risk nor with survival from breast cancer. In summary, this study did not reveal truncating or clearly pathogenic mutations, but unravelled four new unclassified missense variants at a low frequency. We conclude that there is no evidence for a major role of SLX4 coding variants in the inherited susceptibility towards breast cancer in German and Byelorussian patients, although very rare mutations such as the p.G700R substitution could make a minor contribution.

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Section: Patientsmentioning

confidence: 98%

Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer

Landwehr

Bogdanova

Antonenkova

et al. 2011

Breast Cancer Res Treat

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“…All the 13 ATM mutations identified by Renwick et al [16] were predicted to cause A-T, and nine of those identified in cases have previously been reported in A-T families, including the two most common mutations in the UK, c.5762ins137 and c.3802delG. More recently, a study of Bogdanova et al [21] provided evidence for the association of an ATM founder mutation (c.5932G[T; p.E1978X, a common A-T causing mutation) with BC in Eastern European populations. These findings suggest that it is possible to approach carrier testing by first identifying the most common mutations in selected populations and then developing rapid assays that use small amounts of genomic DNA and less costly methods.…”

Section: Introductionmentioning

confidence: 94%

Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry

Graña

Fachal

Darder

et al. 2011

Breast Cancer Res Treat

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Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case-control study to determine the prevalence of 32 known ATM mutations causing A-T in Spanish population in 323 BRCA1/BRCA2 negative hereditary breast cancer (HBC) cases and 625 matched Spanish controls. For the detection of the 32 ATM mutations we used the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique. We identified one patient carrier of the c.8264_8268delATAAG ATM mutation. This mutation was not found in the 625 controls. These results suggest a low frequency of these 32 A-T causing mutations in the HBC cases in our population. Further case-control studies analyzing the entire coding and flanking sequences of the ATM gene are warranted in Spanish BC patients to know its implication in BC predisposition.

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“…Data on ATM, NBS1 (NBN), BRIP1, BLM, etc. are less comprehensive, but nevertheless these genes may also be regarded as substantial contributors to breast cancer risk [8,9,26,[127][128][129][130][131].…”

Section: Breast Cancermentioning

confidence: 99%

“…and subsequent casecontrol study for newly identified variants. This approach allows to reveal even those genes, which are not easily transmitted through generations due to severity of disease manifestation (e.g., TP53 [6]) or characterized by incomplete penetrance (e.g., CHEK2, NBS1 (NBN), ATM, BLM [7][8][9]). …”

Section: Introductionmentioning

confidence: 99%

Identification of novel hereditary cancer genes by whole exome sequencing

et al. 2015

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Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years.

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A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer

Cited by 42 publications

References 24 publications

Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer

Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer

Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry

Identification of novel hereditary cancer genes by whole exome sequencing

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