Tetsuro Noguchi

Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions

To appreciate the involvement of known or potential susceptibility genes in sporadic breast tumors, we have searched for chromosomal deletions by studying loss of heterozygosity (LOH) at 43 microsatellite (CA)n markers from human chromosomes 10, 11 and 17, in 115 unselected consecutive samples of breast carcinoma with particular emphasis on specific regions. No site of consistent LOH was identified on chromosome 10. Five regions of LOH were contained within bands q22-24 of chromosome 11 for which nearly 50% of the tumors had LOH at at least one marker. This region is thus a major site of deletion in breast cancer and several tumor suppressor genes seem to be involved. One of them may be the ataxia telangiectasia (ATM) gene which is located in one of the affected regions. Five regions of LOH, one of which is within the BRCA1 gene area, were recognized along chromosome 17. LOH at three of these regions were found in highly proliferative tumors. When combined with a previous study of chromosome 13 with emphasis on BRCA2 and Rb1 genes, this work allowed to distinguish a total of 12 regions of LOH, variably affected in breast tumors and correlated with prognostic parameters.

Novel indications for BRCA1 screening using individual clinical and morphological features

Since there is a lack of common family profile among BRCA1‐gene carriers, and since the risk of being a mutation carrier is not limited to women with a family history of breast or ovarian cancer, multivariate statistical analysis using the logistic‐regression model was carried out, to discriminate between sporadic cases and BRCA1‐breast cancers (BRCA1‐BCs), especially when information about the family history of breast/ovarian cancer and ethnicity are irrelevant or unavailable, in order to offer specific medical treatment to this population. We examined 32 BRCA1‐BCs selected at cancer genetic clinics and 200 consecutive controls without family history of breast cancer for age at onset and current morphological parameters. Following the multivariate analysis, 3 parameters only, namely, early age at cancer onset [odds ratio (OR) for each year = 1.16; p < 0.0001], estrogen‐receptor negativity (OR = 5.7; p = 0.01) and poor differentiation (OR = 5; p = 0.03) were found significant factors for predicting BRCA1‐carrier status. The expected impact in BRCA1 screening of our model was estimated using data on 5 700 breast‐cancer cases from a hospital‐based registry. Only 50 and 15% of tumours with early age at onset below 35 years present one or the other 2 discriminant parameters respectively. Consequently, whereas the probability of finding a BRCA1 mutation is rated low (6.2%) when the sole criterion of early onset up to the age of 35 years is used, based on our model, in the sub‐group of women with a tumor that is both estrogen‐receptor‐negative and poorly differentiated the mutation‐detection rate is predicted to be above the 10% chance level recommended by the ASCO guidelines. This sub‐group of women, representing about 1% of all breast‐cancer cases in Western countries, consequently deserves to be tested. Int. J. Cancer (Pred. Oncol.) 84:263–267, 1999.