Strong indication for a breast cancer susceptibility gene on chromosome 8p12-p22: linkage analysis in German breast cancer families

Seitz, Susanne; Rohde, Klaus; Bender, E.; Nothnagel, Anita; Kölble, Konrad; Schlag, Peter M.; Scherneck, Siegfried

doi:10.1038/sj.onc.1200881

Cited by 104 publications

(57 citation statements)

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“…10 -12,23 Kerangueven et al 10 and Seitz et al 23 suggested that 8p12-p21 is a locus for a new breast cancer susceptibility gene. Our data do not exclude this possibility and may indeed enhance it.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic analyses on BRCAX patients identified several chromosomal regions potentially harbouring other breast cancer susceptibility genes. They include 8p12-p21, 10 13q21, 11 and 2q32, 12 however, they were excluded or need to be evaluated with regards to population specificity. 13 There are no comprehensive molecular cytogenetic studies that report characteristic chromosomal imbalances involved in tumour progression in BRCAX patients.…”

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confidence: 99%

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Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

Gronwald

Jauch

Cybulski

et al. 2004

Intl Journal of Cancer

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Very little is known about the chromosomal regions harbouring genes involved in initiation and progression of BRCAX-associated breast cancers. We applied comparative genomic hybridization (CGH) to identify the most frequent genomic imbalances in 18 BRCAX hereditary breast cancers and compared them to chromosomal aberrations detected in a group of 27 sporadic breast cancers. The aberrations observed most frequently in BRCAX tumours were gains of 8q (83%), 19q (67%), 19p (61%), 20q (61%), 1q (56%), 17q (56%) and losses of 8p (56%), 11q (44%) and 13q (33% Breast cancer continues to be the leading cause of morbidity and mortality in women throughout much of the developed world. At least 10% of these tumours develop in families with strong aggregations of both breast or ovarian cancers showing an autosomal dominant transmission pattern. 1 The etiology and progression of breast malignancies is associated with a series of genomic alterations. Only germ-line mutations of 2 breast cancer susceptibility genes BRCA1 and BRCA2 have been identified in a significant number of families of patients with breast or ovarian cancer aggregation. 2,3 Mutations in these genes explain the cancer etiology of the majority of breast ovarian cancer families, but only a small proportion of cases with hereditary site-specific breast cancer. 4,5 The risk in women without detectable BRCA1/2 coding region mutations but with a positive family history remains significantly increased. 1 Available data suggest that for at least twothirds of hereditary breast cancers (other than BRCA1/2) autosomal dominant moderate or highly penetrant genes (defined as BRCAX) are likely to exist. 4,5 The involvement of genes predisposing for other family syndromes that show moderately increased breast cancer risk such as PTEN, ATM, TP53, CHEK2 do not contribute significantly to hereditary breast cancer incidence. 6 -9 The failure to identify a third breast cancer susceptibility gene in the list of low-penetrant genes described above strongly suggests that other breast cancer susceptibility genes involved in the initiation of these tumours still remain to be found.Chromosomal segments involved recurrently in gains and losses of primary tumours provide target regions for the search of oncogenes and tumour suppressor genes, respectively, which may be involved in tumour initiation and progression. Genetic analyses on BRCAX patients identified several chromosomal regions potentially harbouring other breast cancer susceptibility genes. They include 8p12-p21, 10 13q21, 11 and 2q32, 12 however, they were excluded or need to be evaluated with regards to population specificity. 13 There are no comprehensive molecular cytogenetic studies that report characteristic chromosomal imbalances involved in tumour progression in BRCAX patients.We applied CGH to identify the most frequent genomic imbalances in BRCAX hereditary breast cancers and compared them to abnormalities detected in a group of breast cancers that were derived from patients who had no evidence of a familial aggrega...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

Gronwald

Jauch

Cybulski

et al. 2004

Intl Journal of Cancer

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“…None of the P-values were significant after the correction of Benjamini and Hochberg [1995] (data not shown). A P-value of 6 Â 10 À4 was obtained at the SNP TSC671100 at 26.8 Mbs on chromosome 8p12, which is within a region previously identified by linkage analysis [Kerangueven et al, 1995;Seitz et al, 1997].…”

Section: Genome-wide Snp Ld Mapping Of the ''Test'' Set Approach To Nmentioning

confidence: 96%

“…Nonetheless, in the analysis of the ''test'' data set, P-values close to the significance threshold obtained after correction for multiple testing were achieved in two regions of the genome: one on chromosome 15, and another on chromosome 9. A third region was identified in the haplotype analysis that was identified previously by linkage analysis [Kerangueven et al, 1995;Seitz et al, 1997]. To determine whether these potential associations can be replicated, haplotype-tagging SNPs from the three candidates regions should be genotyped in the ''test'' set, and thereafter the most informative SNPs should be tested in an independently ascertained series of breast cancer cases and controls.…”

Section: P-value Cutoffs and Replicationmentioning

confidence: 99%

“…However, attempts to utilize linkage to localize other genes associated with an inherited predisposition to cancer have been hampered by genetic heterogeneity, decreased penetrance, and chance clustering [Thompson et al, 2002]. Illustrating these problems, loci identified by linkage on chromosomes 8 and 13 [Kerangueven et al, 1995;Seitz et al, 1997;Kainu et al, 2000] were not confirmed in analyses in other studies [Rahman et al, 2000;Thompson et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

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Localization of breast cancer susceptibility loci by genome‐wide SNP linkage disequilibrium mapping

Ellis

Kirchhoff

Mitra

et al. 2005

Genetic Epidemiology

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We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genomewide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a ''validation'' set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a ''field'' set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a ''test'' set of 57 probands from breast cancer kindreds (4 or more cases/ kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs. controls by the Fisher's exact test and a maximum likelihood ratio test. In the ''validation'' set, we demonstrated the presence of a region of linkage disequilibrium on BRCA2*6174delT chromosomes that spanned over 5 million bases. In the ''field'' set, we showed that this large region of linkage disequilibrium flanking BRCA2 was detectable despite the presence of heterogeneity in the sample set. Finally, in the ''test'' set, at least three regions of interest emerged that could contain novel breast cancer genes, one of which had been identified previously by linkage analysis. While these results demonstrate the feasibility of genome-wide association strategies, further application of this approach will critically depend on optimizing the density and distribution of SNPs and the size and type of study design. Genet. Epidemiol. 30:48-61, 2006. r 2005 Wiley-Liss, Inc.

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Marker segregation information in breast/ovarian cancer genetic counseling: Is it still useful?

et al. 1998

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The use of mutation screening of BRCA1 and BRCA2 genes as a genetic test is still to a certain extent limited and the oncogeneticist may want to use complementary approaches to identify at-risk individuals. In a series of 23 families with at least three breast or ovarian cancer cases, screened for mutations at BRCA1 and BRCA2 and typed for markers at both loci, we investigated the usefulness of marker segregation information at two levels: 1) to what extent can the indirect approach identify the mutation carrier status of screened cases and their first-degree relatives, and 2) in what way does it help to identify the gene implicated in a family in which neither BRCA1 nor BRCA2 mutation has been detected? Using the indirect approach, the carrier status of the screened case could be determined with quasi certainty in three families and with a high probability in eight families. This status could be inferred in unaffected first-degree relatives as almost certain in one family and as highly probable in six families. Fourteen mutations were found concurrently in our series. Among the nine mutation-negative families, we were able to conclude that a BRCA1 mutation most probably segregated in one and that a mutation other than BRCA1 and BRCA2 was probably involved in two families. Our results show that, in small families, little help is to be expected from linkage data and mutation screening is the only way of identifying the origin of a genetic predisposition in a family. Marker segregation information may be useful in some large breast/ovarian cancer families in which no BRCA1 or BRCA2 mutation has been detected.

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Strong indication for a breast cancer susceptibility gene on chromosome 8p12-p22: linkage analysis in German breast cancer families

Cited by 104 publications

References 10 publications

Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

Localization of breast cancer susceptibility loci by genome‐wide SNP linkage disequilibrium mapping

Marker segregation information in breast/ovarian cancer genetic counseling: Is it still useful?

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