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Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals.

Abstract

INTRODUCTION

Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling.

METHODS

Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P).

RESULTS

Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA).

CONCLUSIONS

In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool.

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  • Authors+Show Affiliations

    ,

    Institute of Biomedical Technology, University of Tampere, Biokatu 8, Tampere, 33520, Finland.

    , , ,

    Source

    Breast cancer research : BCR 13:1 2011 Feb 28 pg R20

    MeSH

    Adult
    Aged
    Alleles
    Amino Acid Substitution
    Antigens, CD
    Breast Neoplasms
    Cadherins
    Checkpoint Kinase 2
    DNA Mutational Analysis
    DNA Repair Enzymes
    DNA-Binding Proteins
    Fanconi Anemia Complementation Group N Protein
    Fanconi Anemia Complementation Group Proteins
    Female
    Finland
    Gene Frequency
    Genes, BRCA1
    Genes, BRCA2
    Genes, Tumor Suppressor
    Genetic Predisposition to Disease
    Germ-Line Mutation
    Humans
    MicroRNAs
    Middle Aged
    Mutation
    Nuclear Proteins
    Ovarian Neoplasms
    Pedigree
    RNA Helicases
    Tumor Suppressor Proteins
    Young Adult

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21356067

    Citation

    Kuusisto, Kirsi M., et al. "Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 Mutations in High-risk Finnish BRCA1/2-founder Mutation-negative Breast And/or Ovarian Cancer Individuals." Breast Cancer Research : BCR, vol. 13, no. 1, 2011, pp. R20.
    Kuusisto KM, Bebel A, Vihinen M, et al. Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Res. 2011;13(1):R20.
    Kuusisto, K. M., Bebel, A., Vihinen, M., Schleutker, J., & Sallinen, S. L. (2011). Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Research : BCR, 13(1), pp. R20. doi:10.1186/bcr2832.
    Kuusisto KM, et al. Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 Mutations in High-risk Finnish BRCA1/2-founder Mutation-negative Breast And/or Ovarian Cancer Individuals. Breast Cancer Res. 2011 Feb 28;13(1):R20. PubMed PMID: 21356067.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. AU - Kuusisto,Kirsi M, AU - Bebel,Aleksandra, AU - Vihinen,Mauno, AU - Schleutker,Johanna, AU - Sallinen,Satu-Leena, Y1 - 2011/02/28/ PY - 2010/08/09/received PY - 2010/12/14/revised PY - 2011/02/28/accepted PY - 2011/3/2/entrez PY - 2011/3/2/pubmed PY - 2014/3/26/medline SP - R20 EP - R20 JF - Breast cancer research : BCR JO - Breast Cancer Res. VL - 13 IS - 1 N2 - INTRODUCTION: Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling. METHODS: Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P). RESULTS: Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA). CONCLUSIONS: In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool. SN - 1465-542X UR - https://www.unboundmedicine.com/medline/citation/21356067/Screening_for_BRCA1_BRCA2_CHEK2_PALB2_BRIP1_RAD50_and_CDH1_mutations_in_high_risk_Finnish_BRCA1/2_founder_mutation_negative_breast_and/or_ovarian_cancer_individuals_ L2 - https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr2832 DB - PRIME DP - Unbound Medicine ER -