BRCA1‐related breast cancer in Austrian breast and ovarian cancer families: Specific BRCA1 mutations and pathological characteristics

Wagner, Teresa; Möslinger, R.; Muhr, Daniela; Langbauer, Gudrun; Hirtenlehner, Kora; Concin, Hans; Doeller, Walter; Haid, A.; Lang, Alois; Mayer, Péter; Ropp, Erich; Kubista, E.; Amirimani, Benoosh; Helbich, Thomas H.; Becherer, Alexander; Scheiner, Otto; Breiteneder, Heimo; Borg, Åke; Devilee, Peter; Oefner, Peter J.; Zielinski, Christoph

doi:10.1002/(sici)1097-0215(19980729)77:3<354::aid-ijc8>3.3.co;2-a

Cited by 43 publications

(55 citation statements)

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“…Twenty-five different BRCA1 and 28 distinct BRCA2 mutations appear to be unique to the German population. BRCA1 mutations previously found in neighboring countries such as Austria (2795del4bp) 31 and The Netherlands (2804delAA and IVS21-35del510bp) 10,32 were also identified in our breast cancer population. Common mutations in the German patient group include sequence changes such as 5382insC 33 and 300T3 G that have been found frequently in multiple, apparently diverse populations.…”

Section: Mutation Spectrum For German Breast/ovarian Cancer Familiessupporting

confidence: 70%

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

2001

Intl Journal of Cancer

192

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The main focus of this German-wide multi-center study was to establish a BRCA1/2 mutation profile and to determine family types with high frequencies of mutations in these genes. In a comprehensive study, the entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were analyzed in 989 unrelated patients from German breast/ovarian cancer families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious mutations were found in 302 patients. More than 1 ⁄3 of these mutations are novel and might be specific for the German population. Eighteen common mutations were found in 68% of cases in BRCA1 and 13 recurrent mutations in 44% of cases in BRCA2, facilitating prescreening approaches. Haplotype analysis indicate that 14 out of 20 recurrent mutations are likely originating from a common founder. An additional 50 different rare sequence variants with unknown relevance for tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2 detection rates with family history identified families with both breast and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43% and 10%, respectively), followed by families with at least 2 premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2 mutations). These data provide strong evidence for further predisposing genes in the German population. In breast cancer families with 2 or 3 affected females but only a single or no premenopausal case, mutations were detected with low frequencies (about 10% or less for both genes). The decision for or against molecular diagnosis is now aided by considering the expected mutation detection rates that greatly depend on family history and structure.

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Section: Mutation Spectrum For German Breast/ovarian Cancer Familiessupporting

confidence: 70%

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

2001

Intl Journal of Cancer

192

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“…This recurrent mutation 4 is recorded in several databases 10,12,13 and has been previously observed in Austria, albeit with lower frequencies than in our cohort. 11,14 We found this mutation only in individuals who lived in the Tyrol, an alpine province characterized by confined valleys separated by huge mountain ranges historically forming isolates. Intriguingly, the c.4183C4T mutation was responsible for 475% of seemingly unrelated HBOC families in the LIV region, and in particular the major side valley Zillertal.…”

Section: Discussionmentioning

confidence: 78%

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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“…21 In addition, gels need to be exposed to a sensitive film for a variable length of time, and the interpretation of band patterns can be cumbersome for the inexperienced eye. Denaturing HPLC has been successfully applied in the mutation detection of BRCA1 gene, [27][28][29] PTEN, 30,31 and the tuberous sclerosis genes TSC1 and TSC2. 24,32 It has been estimated that the sensitivity of the detection is greater than 95%; 30 similar or superior to that obtained by SSCP.…”

Section: Resultsmentioning

confidence: 99%

Validation of Denaturing High Performance Liquid Chromatography as a Rapid Detection Method for the Identification of Human INK4A Gene Mutations

Orlow

Roy

Barz

et al. 2001

The Journal of Molecular Diagnostics

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The incidence of melanoma is increasing rapidly in western countries. Genetic predisposition in familial and in some sporadic melanomas has been associated with the presence of INK4A gene mutations. To better define the risk for developing sporadic melanoma based on genetic and environmental interactions, large groups of cases need to be studied. Mutational analysis of genes lacking hot spots for sequence variations is time consuming and expensive. In this study we present the application of denaturing high performance liquid chromatography (DHPLC) for screening of mutations. Exons 1␣, 2, and 3 were amplified from 129 samples and 13 known mutants, yielding 347 products that were examined at different temperatures. Forty-two of these amplicons showed a distinct non-wild-type profile on the chromatogram. Independent sequencing analysis confirmed 16 different nucleotide variations in Leu 32 Pro; Ile49Thr; 88 del G; Gln50Arg; Arg24Pro; Met53Ile; Met53Thr; Arg58stop; Pro81Leu; Asp84Ala; Arg80stop; Gly101Trp; Val106Val; Ala148Thr; and in positions (؊2) in intron 1 (C 3 T); and in the 3 UTR, nucleotide 500 (C 3 G). No false negatives or false positives were obtained by DHPLC in samples with mutations or polymorphisms. We conclude that the DHPLC is a fast, sensitive, cost-efficient, and reliable method for the scanning of Cutaneous melanomas are being detected at an increasing rate worldwide. Even though many patients are diagnosed at an early stage, the death rate continues to rise due to the increasing incidence of more advanced lesions. 1,2 Genetic and environmental factors such as family history, skin type, previous tumors, and sun exposure have been identified as important risk factors. [3][4][5][6] In addition, germline mutations or variants of certain genes have been proposed as risk factors for the development of melanomas. One of these genes, the CDKN2A or INK4A, encodes for p16, an important cell cycle regulator capable of arresting cells in G1-phase by inhibiting the phosphorylation of the retinoblastoma protein by cyclinD1/Cdk4 complexes. 7 The INK4A gene has been found silenced by point mutation, deletion, and methylation of the promoter region in several sporadic tumor types. 8 -16 Analyses of INK4A in sporadic melanomas revealed a frequency of mutations and deletions that ranges from approximately 75% in cell lines 8 to 15% in primary multiple melanoma tumors. 17 In addition, INK4A germline mutations have been found in melanoma kindreds, ranging in prevalence from 10.3 to 72.2%, 18 -19 although in overall approximately 20% of the families that have been studied show mutations in this gene. 20 In an attempt to better define the gene-environment interactions in sporadic melanoma, our group expects to enroll 4000 newly diagnosed subjects to determine the relationship between germline INK4A mutations and environmental factors such as sun exposure. Typically, INK4A gene mutations have been analyzed by polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) and sequencing. 16,18,21 D...

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BRCA1‐related breast cancer in Austrian breast and ovarian cancer families: Specific BRCA1 mutations and pathological characteristics

Cited by 43 publications

References 0 publications

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

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

Validation of Denaturing High Performance Liquid Chromatography as a Rapid Detection Method for the Identification of Human INK4A Gene Mutations

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