"Investigation of the prevalence of germline mutations in BRCA1 and BRCA2 in women with breast cancer diagnosed before thirty years of age or with a strong family history"

Dr Shirley Hodgson 1
Dr David Ellis 1
Ms Jill Greenman 1
Ms June Cameron 1
Dr Louise Izatt 1
Ms Gillian Scott 1
Ms Chris Jacobs 1
Mrs Sally Watts 1
Ms Wendy Chorley 2
Dr Christopher Perrett 2
Dr Kay MacDermott 2
Dr D. G. Evans 3
Professor Christopher Mathew 1

Division of Medical & Molecular Genetics, UMDS Guy's & St. Thomas' Hospitals, London
2 University Department of Obstetrics & Gynaecology, Royal Free Hospital School of Medicine, London
3 St. Mary's Hospital, London

Executive Summary


To assess the prevalence of germline BRCA1 gene mutations in breast cancer patients with either early-onset sporadic disease or a family history of breast and/or ovarian cancer.


The majority of referrals to genetic family cancer clinics are of individuals with only a moderate family history of breast and/or ovarian cancer, and such referrals are increasing rapidly. Prioritisation of families for genetic testing, in the context of limited resources, is essential for the development of cost effective services. In order to assess the likely contribution of germline mutations in genes conferring a high risk of breast cancer in these referrals, we have ascertained two groups of women affected with breast cancer. The first is women affected at a young age, but with no known family history of breast/ovarian cancer, and the second a group of affected women with a limited family history of breast/ovarian cancer (with at least one breast cancer diagnosed below 45 years of age), characteristic of families currently referred.


Patients were ascertained from referrals to family cancer clinics in the Genetics Department at Guy's Hospital, the Royal Free Hospital, and St. Mary's Hospital, Manchester, and patients seen at the ICRF Breast Oncology Unit at Guy's Hospital.


345 unrelated patients with breast cancer


(i)      Design of a sensitive, robust and cost-effective strategy to screen breast      cancer predisposition genes for mutations;
(ii)     Determination of the prevalence of mutations in different patient groups.


A mutation detection protocol was developed which uses multiplex amplification of exons from genomic DNA and flourescent chemical cleavage of mismatch to screen the entire coding sequence of the BRCA1 gene with high sensitivity.
Germline BRCA1 mutations were detected in 28 of 345 patients (8.1%) overall. Detection rates ranged from 3.6% (5/139) in young sporadic cases with a diagnosis before 45 years of age, to 18.2% (10/55) in patients with a family history of both breast and ovarian cancer. Detection rates in site specific familial breast cancer were intermediate at 8.6% (13/151), although families with 3 cases had the highest prevalence in this group (7/47 or 14.9%). Surprisingly, families with 4 or more cases of breast cancer but no ovarian cancer had the lowest rate (1/48 or 2.1%). Several missense mutations were also detected which met established criteria for pathogenic mutations.


These findings suggest that patients with a modest family history of site specific breast cancer, or of breast and ovarian cancer, have a significant prevalence of germline mutations in the BRCA1 gene, whereas young sporadic patients are much less likely to have mutations. These findings have important implications for future mutation screening policy in early onset and familial breast cancer.


Ellis D., Greenman J., Izatt L., MacDermot K., Perrett C., Evans G., Hodgson S., and Mathew C. (1998) Rapid mutation screening of the BRCA1 gene in early onset sporadic and familial breast cancer patients using chemical cleavage of mismatch analysis (Abstract 02.38, British Human Genetics Conference, 28-30.9.98, York). J Med Genet 35 (suppl 1), S43.

Greenman J., Mohammed S., Ellis D., Watts S., Scott G., Izatt L., Barnes D., Solomon E., Hodgson S., and Mathew C. (1998) Identification of missense and truncating mutations in the BRCA1 gene in sporadic and familial breast and ovarian cancer. Genes Chromosom Cancer 21, 244-249.

Hodgson S. V., Heap E., Cameron J., Ellis D., Mathew C., Eeles R., Solomon E., and Lewis C. M., (1998) Logistic modelling for the probability of detecting germline ancestral BRCA1, BRCA2 and mutations in Ashkenazi Jewish women in the U.K. affected with breast or ovarian cancer. J Med Genet, in press.

Hodgson S., Lewis C. M., Heap E., Cameron J., and Soloman E. (1998) Prevalence of specific germline mutations in BRCA1 and BRCA2 in women affected with breast or ovarian cancer from the Ashkenazi Jewish population (Abstract P1.007, 30th Annual Meeting, European Society of Human Genetics, Lisbon, Portugal, 10-13.5.98). Eur J Hum Genet 6 (suppl 1), 46.

Hodgson S., Lewis C. M., Heap E., Eeles R., Cameron J., Ellis D., Mathew C., and Soloman E. (1998) Analysis of the prevalence of specific ancestral germline mutations in BRCA1 and BRCA2, and APC, in women affected with breast or ovarian cancer from the Ashkenazi Jewish population: correlation with pedigree data (Abstract 02.27, British Human Genetics Conference, 28-30.9.98, York).  J Med Genet 35 (suppl 1), S41.

Jacobs C., Hodgson S., Bish A., Sutton S., and Ramirez A. (1998) Evaluation of factors influencing interest in having a test for a genetic susceptibility to breast and/or ovarian cancer and the psychological impact of such testing (Abstract 06.28, British Human Genetics Conference, 28-30.9.98, York). J Med Genet 35 (suppl 1), S69.

Further information may be obtained from:

Dr Shirley V Hodgson
Consultant in Clinical Genetics
UMDS Guy's, King's & St. Thomas' Hospitals
South Thames Regional Genetics Centre (East)
8th Floor, Guy's Tower
Guy's Hospital
St. Thomas
London, SE1 9RT



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