Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA).

Carmel Apicella,Lesley Andrews,Deon J Venter,John L Hopper,Melissa C Southey,Michael Friedlander,Shirley V Hodgson,Sheila A Fisher,Agnes Bankier,Cathryn M Lewis,Ellen Solomon,Katherine Tucker

doi:10.1186/bcr644

Abstract

Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer. Women considering mutation testing usually have several personal and family cancer characteristics, so predicting mutation status from one factor alone could be misleading. The aim of this study was to develop a simple algorithm to estimate the probability that an Ashkenazi Jewish woman carries an ancestral mutation, based on multiple predictive factors. We studied Ashkenazi Jewish women with a personal or family history of breast or ovarian cancer and living in Melbourne or Sydney, Australia, or with a previous diagnosis of breast or ovarian cancer and living in the UK. DNA samples were tested for the germline mutations 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. Logistic regression was used to identify, and to estimate the predictive strength of, major determinants. A mutation was detected in 64 of 424 women. An algorithm was developed by combining our findings with those from similar analyses of a large study of unaffected Jewish women in Washington. Starting with a baseline score, a multiple of 0.5 (based on the logistic regression estimates) is added for each predictive feature. The sum is the estimated log odds ratio that a woman is a carrier, and is converted to a probability by using a table. There was good internal consistency. This simple algorithm might be useful in the clinical and genetic counselling setting. Comparison and validation in other settings should be sought.

Highlights

Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer
Subjects In Australia, eligible women were self-identified as being of Ashkenazi Jewish descent, living in Melbourne or Sydney, who had reported either having had a previous diagnosis of breast or ovarian cancer themselves, or having a firstdegree or second-degree relative who had been diagnosed with breast or ovarian cancer
Statistical methods Unconditional multiple linear logistic regression was used to model the probability that the proband was a mutation carrier as a function of her personal and family history, and either age at diagnosis of first cancer if the index person had a previous diagnosis of breast or ovarian cancer, or age at testing if unaffected

Summary

Introduction

Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer. Personal factors include a previous history of breast or ovarian cancer, especially if breast cancer was diagnosed at a relatively early age, and bilateral disease or both cancers in the same woman [3,4,5,6,7,8,9,10]. The occurrence of these factors in close relatives has been found in general to be predictive, but the strength of prediction is weaker and the conclusions are less definitive

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