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Analysis of Cancer Risk and BRCA1 and BRCA2 Mutation Prevalence in the kConFab Familial Breast Cancer Resource


Analysis of Cancer Risk and BRCA1 and BRCA2 Mutation Prevalence in the kConFab Familial Breast Cancer Resource

Graham J Mann et al. Breast Cancer Res.


Introduction: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives.

Methods: Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study.

Results: Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue--both normal and malignant--including 126 from carriers of BRCA1 or BRCA2 mutations.

Conclusion: These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.


Figure 1
Figure 1
Relationship between estimated cumulative probability and actual relative frequency of breast cancer since ascertainment. Women unaffected at time of interview were ranked in quintiles according to their cumulative risk of breast cancer since interview, calculated from the absolute risk estimated by a batch program implementing the Tyrer-Cuzick algorithm. The proportion of women in each risk quintile (horizontal axis: 1 lowest to 5 highest) developing breast cancer during a median 4.2 years follow-up is plotted on the vertical axis plus standard error. (a) All families; (b) BRCA1 or BRCA2 mutation positive families; (c) BRCA1 or BRCA2 mutation negative families.
Figure 2
Figure 2
Relationship between estimated probability and predicted relative frequency or BRCA1 and BRCA2 mutations. Women unaffected at time of interview were ranked in quintiles according to their probability of carrying either a (a) BRCA1 or (b) BRCA2 mutation, as estimated by a batch program implementing the Tyrer-Cuzick algorithm, without input of family or individual mutation status. The proportion of women that tested positive for either a BRCA1 (open bars) or BRCA2 (closed bars) mutation is plotted on the vertical axis.

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