The Use of Ancestral Haplotypes in the Molecular Diagnosis of Familial Breast Cancer

Frosk, Patrick; Burgess, Susan; Dyck, Tamara; Jobse, Rick; Spriggs, Elizabeth L.

doi:10.1089/gte.2006.0518

Cited by 6 publications

(7 citation statements)

References 17 publications

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“…Evaluation of the regional origin of these families revealed that 11 of them were from the LIV region, with the majority from the Zillertal, a large connected side valley of this region. Assessment of sequencing data in informative c.4183C4T mutation carriers showed that with the exception of a patient from Germany, all 13 c.4183C4T mutation carriers from the Tyrol had SNV genotypes compatible with a haplotype described as B1 allele by Frosk et al 9 Genotyping of all 13 Tyrolean c.4183C4T mutation carriers in the diagnostic cohort was compatible with a common haplotype c. High prevalence of BRCA1 mutation c.4183C4T in unselected Tyrolean breast and ovarian cancer patients More than 75% (11/14) of molecularly confirmed HBOC families from the LIV region carried the founder mutation c.4183C4T. To assess the prevalence of this mutation in a larger number of individuals, we examined a total of 219 breast and 59 ovarian cancer samples from unselected patients living in that region.…”

Section: Materials and Methods Patientsmentioning

confidence: 93%

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

et al. 2015

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Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c. 4183C4T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C4T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region. European Journal of Human Genetics (2016) 24, 258-262; doi:10.1038/ejhg.2015.108; published online 27 May 2015 INTRODUCTIONA central aim of preventive oncology is the identification of patients with a heritable predisposition to cancer. An estimated 1-7% of unselected breast cancer patients 1-4 and 6-17% of women with ovarian cancer 5,6 have hereditary breast and ovarian cancer (HBOC) disposition caused by variants in either BRCA1 or BRCA2 that confer a high risk of developing cancer. In agreement with a widely used terminology, such variants will be called mutations throughout this paper. Because of high costs, comprehensive molecular analyses for HBOC are usually restricted to individuals with a suggestive family history, young age, or several independent tumours. Tumour characteristics (triple-negative breast cancer; TNBC) are also used for the identification of patients with a high probability of carrying a BRCA mutation. 7,8 Reduced costs of novel sequencing methods and better knowledge of the clinical relevance of alterations in BRCA1 and BRCA2 will increase the number of individuals eligible for sequence analysis, although some selection process will still remain necessary in the foreseeable future. Identification of common founder mutations in certain ethnicities allows integration of genetic testing strategies in the routine care of all cancer patients. Here we report the identification of a highly prevalent BRCA1 founder mutation in a particular region of the Tyrol and consider the implications for a screening programme offered to all breast and ovarian cancer patients in this region.

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Section: Materials and Methods Patientsmentioning

confidence: 93%

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

et al. 2015

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“…BRCA1 is hypothesized to be a locus under recombination inhibition, and very few haplotypes have been described here [5]. Frosk et al [6] in their recent study identified eight distinct haplotypes in BRCA1, mostly derivates of two main lineages. In BRCA2, 17 distinct haplotypes were reported, indicating more complex polymorphic pattern in this gene.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia

Konečný

Milly

Zavodna

et al. 2011

Breast Cancer Res Treat

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Germline mutations in the BRCA1/2 genes account for the majority of hereditary breast ovarian cancer (HBOC).Identification of causal mutations may have significant impact on clinical management of such families. Despite high mutation detection rate, many HBOC cases remain without identified cause. These cases warrant use of several analysis methods, such as those for large genomic rearrangements and DNA copy number changes, or analysis other genes, shown to be associated with increased HBOC risk.We assessed 585 Slovak HBOC for presence of mutations in BRCA genes. Sequencing revealed mutations in 100 families, representing 17.1% (88% and 12% of mutations were located in BRCA1 and BRCA2, respectively).Four of the mutations, c.80+4del4, c.1938_1947del10 and c.1166delG in BRCA1 and c.6589delA in BRCA2 gene have been described only in Slovak population. Using MLPA analysis, we detected two large genomic rearrangements in 3 families, a deletion of exons 21 and 22, and a rare deletion of a whole BRCA1 gene. Twentyseven different variants of uncertain clinical effect (4 novel) and 14 distinct SNP BRCA1 haplotypes were detected. Their potential effect was considered using the prediction software packages Align GVGD, Pmut and Polyphen.We observed that the best clinical criterion for the initiation of BRCA1 analysis is the presence of breast cancer at 40 years of age in the association with the presence of ovarian cancer diagnosed around the age of 50.Conversely, the best clinical criterion for starting with BRCA2 analysis is the presence of breast cancer diagnosed in older age (above 50), or the presence of breast cancer in conjunction with carcinomas at different sites e.g. prostate, colorectum, ovary, uterus. Finally we have seen that the analyses of other HBOC risk gene TP53 and specific mutation in CHEK2*c.1100delC in Slovak HBOC families were not efficient since no mutations were found in these genes. 2

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“…To determine relatedness between families identified with BRCA1 promoter methylation, we genotyped 12 BRCA1 intragenic SNPs by Sanger sequencing to determine ancestral haplotypes (Supplemental Material and Methods). 20 In addition, genotyping using Affymetrix Genome-Wide SNP6.0 arrays was undertaken according to the manufacturer’s protocol. Genotypes and copy-number data were generated within the Affymetrix Genotyping Console (v.4.1.3.840) via the Birdseed V2 algorithm and SNP 6.0 CN/LOH algorithm, respectively.…”

Section: Methodsmentioning

confidence: 99%

A Dominantly Inherited 5′ UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer

Evans

Veen

Byers

et al. 2018

The American Journal of Human Genetics

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Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5' UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.-107A>T in the BRCA1 5' UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5' UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.

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The Use of Ancestral Haplotypes in the Molecular Diagnosis of Familial Breast Cancer

Cited by 6 publications

References 17 publications

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia

A Dominantly Inherited 5′ UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer

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