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Large genomic rearrangements in the familial breast and ovarian cancer gene BRCA1 are associated with an increased frequency of high risk features

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Abstract

Large genomic rearrangements (LGRs) account for at least 10 % of the mutations in BRCA1 and 5 % of BRCA2 mutations in outbred hereditary breast and ovarian cancer (HBOC) families. Data from some series suggest LGRs represent particularly penetrant mutations. 1,034 index cases from HBOC families underwent comprehensive BRCA1 and BRCA2 mutation testing, including screening for LGRs. The personal and family history of 254 identified mutation carriers were compared based on mutation type. Thirty-six LGRs were detected; 32/122 (26 %) BRCA1 and 4/132 (3 %) BRCA2 mutations. High risk features (bilateral breast cancer, diagnosis <40 years, ovarian cancer, male breast cancer) were more commonly associated with an LGR than a non-LGR mutation (p = 0.008), In families with a BRCA1 LGR the mean age of breast cancer diagnosis was younger than in families with a non-LGR BRCA1 mutation (42.5 vs. 46.1 years, p = 0.007). Across the entire group of mutation positive families the number of relatives affected by breast or ovarian cancer was increased [LGR 3.7 vs. non- LGR 2.8 per family, p value (adjusted for genotype) = 0.047]. Excluding index cases, the odds ratio for breast cancer in BRCA1 families with an LGR was 1.42 (95 % CI 1.24–1.63) and for ovarian cancer 1.66 (95 % CI 1.10–2.49). The increased cancer risk was reflected in significantly higher risk assessments by mutation prediction tools. LGRs are associated with higher cancer risks. If validated, LGRs could be included in cancer risk prediction tools to improve personalised cancer risk prediction estimates and may guide cost-minimising mutation screening strategies in some healthcare settings.

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Abbreviations

BMI:

Body mass index

CBC:

Contralateral breast cancer

CIMBA:

Consortium of Investigators of the Modifiers of BRCA1/2 Alleles

DHPLC:

Denaturing high performance liquid chromatography

DNA:

Deoxyribonucleic acid

FCC:

Familial Cancer Centre

HBOC:

Hereditary breast and ovarian cancer

LGR:

Large genomic rearrangement

MLPA:

Multiplex ligation-dependent probe amplification

OCCR:

Ovarian cancer cluster region

PCR:

Polymerase chain reaction

PTT:

Protein truncation test

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Acknowledgments

The authors gratefully acknowledge the assistance of Rebecca Driessen and Kylie Shackleton for the Victorian Familial Cancer Clinical Trials Group, along with Megan Rehfisch, Steven Macaskill, Ayiguli Ha, Jamie Thiessen, Elvina Johnston, Chris Michael-Lovatt and the Genetic Counsellors of the Victorian FCCs. This study was supported by funding from the Department of Health, Victoria (Australia). The Victorian Familial Cancer Clinical Trials Group was supported by the Victorian Cancer Agency (EOI09-50). GJL was supported by a NHMRC research fellowship, the Victorian Breast Cancer Research Consortium and State Government Operational Infrastructure Support.

Conflict of interests

The author(s) declare that they have no competing interests.

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Authors and Affiliations

  1. Familial Cancer Centre, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia

    Paul A. James, Sarah Sawyer, Mary-Anne Young, Rebecca Doherty, Joanne McKinley, Kathryn Alsop & Gillian Mitchell

  2. Molecular Pathology Department, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia

    Samantha Boyle, Serguei Kovalenko, Victoria Beshay & Stephen Fox

  3. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia

    Paul A. James, Stephen Fox & Gillian Mitchell

  4. Familial Cancer Centre, Monash Medical Centre, Clayton Road, Clayton, VIC, 3168, Australia

    Marion Harris

  5. Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3050, Australia

    Geoffrey J. Lindeman

  6. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia

    Geoffrey J. Lindeman

  7. Department of Medicine, University of Melbourne, Parkville, VIC, 3010, Australia

    Geoffrey J. Lindeman

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  1. Paul A. James
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  2. Sarah Sawyer
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  8. Kathryn Alsop
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  12. Geoffrey J. Lindeman
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  13. Gillian Mitchell
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Correspondence to Gillian Mitchell.

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James, P.A., Sawyer, S., Boyle, S. et al. Large genomic rearrangements in the familial breast and ovarian cancer gene BRCA1 are associated with an increased frequency of high risk features. Familial Cancer 14, 287–295 (2015). https://doi.org/10.1007/s10689-015-9785-0

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  • DOI: https://doi.org/10.1007/s10689-015-9785-0

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