Highlights
- •Incidence novel mutations.
- •Characterization of splice variants.
- •Incidence of genomic rearrangements.
Germline mutations in the BRCA1 and BRCA2 genes are associated with hereditary predisposition to breast and ovarian cancer.
Sensitive and accurate detection of BRCA1 and BRCA2 mutations is crucial for personalized clinical management of individuals affected
by breast or ovarian cancer, and for the identification of at-risk healthy relatives.
We performed molecular analysis of the BRCA1 and BRCA2 genes in 898 Greek families, using Sanger sequencing or Next Generation Sequencing
for the detection of small insertion/deletion frameshift, nonsynonymous, truncating
and splice-site alterations and MLPA for the detection of large genomic rearrangements.
In total, a pathogenic mutation was identified in 12.9% of 898 families analyzed.
Of the 116 mutations identified in total 9% were novel and 14.7% were large genomic
rearrangements.
Our results indicate that different types of mutational events in the BRCA1 and BRCA2 genes are responsible for the hereditary component of breast/ovarian cancer in the
Greek population. Therefore the methodology used in the analysis of Greek patients
must be able to detect both point and small frameshift mutations in addition to large
genomic rearrangements across the entire coding region of the two genes.
Keywords
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References
- The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.Cancer Res. 2000; 60: 4513-4518
- Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium.Am J Hum Genet. 1998; 62: 676-679
- Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast cancer linkage consortium.Am J Hum Genet. 1995; 56: 265-271
- Risks of cancer in BRCA1-mutation carriers. Breast cancer linkage consortium.Lancet. 1994; 343: 692-695
- Breast cancer genetics: what we know and what we need.Nat Med. 2001; 7: 552-556
- Functions of BRCA1 and BRCA2 in the biological response to DNA damage.J Cell Sci. 2001; 114: 3591-3598
- Roles of BRCA1 in DNA damage repair: a link between development and cancer.Hum Mol Genet. 2003; 12: R113-R123
- The breast cancer information core: database design, structure, and scope.Hum Mutat. 2000; 16: 123-131
- ClinVar: public archive of interpretations of clinically relevant variants.Nucleic Acids Res. 2016; 44: D862-D868
- Population genetics of BRCA1 and BRCA2.Am J Hum Genet. 1997; 60: 1013-1020
- Ethnic differences in cancer risk resulting from genetic variation.Cancer. 1999; 86: 2575-2582
- Increased risk for familial ovarian cancer among Jewish women: a population-based case-control study.Genet Epidemiol. 1998; 15: 51-59
- Different genomic rearrangements account for 17% of BRCA1/2mutations in Greece.Cancer Res. 2015; 75 (P1–03-08)
- Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families.Hum Mol Genet. 2003; 12: 1055-1061
- BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients.Nat Genet. 1997; 17: 341-345
- Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method.Cancer Res. 2003; 63: 1449-1453
- Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark.Cancer Genet Cytogenet. 2006; 168: 168-171
- Large genomic deletions inactivate the BRCA2 gene in breast cancer families.J Med Genet. 2005; 42: e64
- Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families.J Med Genet. 2005; 42: e31
- Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families.Breast Cancer Res Treat. 2010; 123: 581-585
- Cooperative family registry for breast cancer studies: comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations.Hum Mutat. 2002; 20: 65-73
- A comparison of BRCA1 mutation analysis by direct sequencing, SSCP and DHPLC.Hum Genet. 1999; 105: 72-78
- Sequencing technologies—the next generation.Nat Rev Genet. 2010; 11: 31-46
- Genome sequencing in microfabricated high-density picolitre reactors.Nature. 2005; 437: 376-380
- Best practice guidelines for the use of next-generation sequencing applications in genome diagnostics: a national collaborative study of Dutch genome diagnostic laboratories.Hum Mutat. 2013; 34: 1313-1321
- Development of a next-generation sequencing method for BRCA mutation screening: a comparison between a high-throughput and a benchtop platform.J Mol Diagn. 2012; 14: 602-612
- Molecular analysis of the breast cancer genes BRCA1 and BRCA2 using amplicon-based massive parallel pyrosequencing.J Mol Diagn. 2012; 14: 623-630
- Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments.Hum Mutat. 2002; 20: 218-226
- Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification.Nucleic Acids Res. 2002; 30: e57
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 175: 405-424
- Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies.Hum Mol Genet. 2015; 24: 2125-2137
- Human splicing finder: an online bioinformatics tool to predict splicing signals.Nucleic Acids Res. 2009; 379: e67
- Characterization of a novel large deletion and single point mutations in the BRCA1 gene in a Greek cohort of families with suspected hereditary breast cancer.BMC Cancer. 2004; 4: 61
- Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients.Breast Cancer Res Treat. 2008; 107: 431-441
- Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families in Southern Germany.Hum Mutat. 2003; 22: 259
- BRCA1 and BRCA2 mutation testing in Cyprus; a population based study.Clin Genet. 2017; (Epub ahead of print)https://doi.org/10.1111/cge.12886
- Novel genomic rearrangements in the BRCA1 gene detected in Greek breast/ovarian cancer patients.Eur J Cancer. 2007; 43: 443-453
- Haplotype analysis reveals that the recurrent BRCA1 deletion of exons 23 and 24 is a Greek founder mutation.Clin Genet. 2017; (Epub ahead of print)https://doi.org/10.1111/cge.12824
- Variants of unknown significance in BRCA testing: impact on risk perception, worry, prevention and councelling.Ann Oncol. 2013; 24: viii69-viii74
- Variants of uncertain significance in BRCA testing: evaluation of surgical decisions, risk perception, and cancer distress.Clin Genet. 2013; 84: 464-472
- Meeting the challenges of interpreting variants of unknown clinical significance in BRCA testing.N Z Med J. 2015; 128: 56-61
Article info
Publication history
Published online: October 19, 2017
Accepted:
October 12,
2017
Received in revised form:
October 9,
2017
Received:
December 22,
2016
Footnotes
Funding: This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
