NHS R&D National Cancer Programme
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
Completed: September 1998
Total Cost: £120,546
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
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 Hospial, London
EXECUTIVE SUMMARY
OBJECTIVE
To assess the prevalence of germline BRCA1 gene mutations in breast cancer patients with either earlyonset sporadic disease or a family history of breast and/or ovarian cancer.
DESIGN/ASCERTAINMENT
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
breats/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.
SETTING
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.
NHS R&D National Cancer Programme
SUBJECTS
345 unrelated patients with breast cancer
MAIN OUTCOME MEASURES
(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.
RESULTS
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.
CONCLUSIONS
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.
Publications resulting from the research
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, 2830.9.98, 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.
NHS R&D National Cancer Programme
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.
The views presented here are those of the authors and not necessarily those of the Department of
Health
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