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

Abstract

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 speci®c regions. No site of consistent LOH was identi®ed 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 a ected 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 a ected in breast tumors and correlated with prognostic parameters.

Strong indication for a breast cancer susceptibility gene on chromosome 8p12-p22: linkage analysis in German breast cancer families

“…These ®ndings considerably strengthen earlier suggestions of a third breast cancer susceptibility locus (BRCA3) mapping to a segment on proximal 8p between NEFL and D8S505 encompassing approximately 20 cM (Kerangueven et al, 1995;Imbert et al, 1996). These data were based mainly on cumulative linkage analyses of eight French families, whose individual lod scores did not signi®cantly exceed 0.5 for NEFL-D8S259 (Kerangueven et al, 1995).…”

“…These data were based mainly on cumulative linkage analyses of eight French families, whose individual lod scores did not signi®cantly exceed 0.5 for NEFL-D8S259 (Kerangueven et al, 1995).…”

“…Several candidate regions potentially harbouring such genes have been suggested on the basis of linkage and mutational analyses, including 6q25 around the estrogen receptor (ESR) locus (Zuppan et al, 1991) and 8p12-p22 (Kerangueven et al, 1995;Imbert et al, 1996). Losses of heterozygosity at proximal 8p have been observed in a range of apparently sporadic epithelial carcinomas, including breast cancer (Devilee et al, 1991;Knowles et al, 1993;Kelemen et al, 1994;Shibagaki et al, 1994;Wasylyshyn et al, 1991;Emi et al, 1992;Cliby et al, 1993;Macoska et al, 1995), indicative of the presence of at least one tumor suppressor gene.…”

Multiple target sites of allelic imbalance on chromosome 17 in Barrett's oesophageal cancer

“…A high incidence of LOH on the p arm of chromosome 17 and mutation of the P53 TSG at 17p13.1 are already well established features associated with the development of BOA, and there have been several studies reporting LOH frequencies at the P53 locus ranging from as high as 90 ± 100% (Gonzalez et al, 1997;Blount et al, 1994;Barrett et al, 1996b). Furthermore, in many tumours chromosome 17 is one of the most important targets of LOH and numerous studies testify to highly complex patterns of allelic imbalance a ecting many di erent regions of this chromosome (Cornelis et al, 1993;Phillips et al, 1993;Cropp et al, 1993;Nagai et al, 1995;Kirchweger et al, 1994;Kerangueven et al, 1997;Fong et al, 1995;Neideracher et al, 1997., Phelan et al, 1998. We have conducted our study in anticipation of a similar complexity of LOH on chromosome 17 in Barrett's tumours, and a complication in discerning whether or not additional targets to p53 exist on 17p.…”

“…A region at 17q21 close to but distinct from BRCA1 has also been described that contains the candidate genes nm23.H1, plakoglobin and prohibitin (Sato et al, 1992;Alessandra et al, 1995;Aberle et al, 1995). Moreover, numerous other distinct regions of allelic imbalance have been reported on chromosome 17 suggesting the presence of multiple other TSGs on this chromosome (Cornelus et al, 1993;Phillips et al, 1993;Cropp et al, 1993;Nagai et al, 1995;Kirchweger et al, 1994;Kerangueven et al, 1997;Fong et al, 1995;Neideracher et al, 1997;Phelan et al, 1998).…”