Loss of heterozygosity (LOH) or allelic imbalance, the latter term referring to both loss and gain of an allele, on the long arm of chromosome 16 has been repeatedly found in cancers of, e.g., the breast and prostate. This indicates the presence of one or more tumor suppressor genes on 16q. To locate the gene(s) more precisely, a detailed allelic imbalance map of 20 polymorphic markers on this chromosome arm was made for 79 sporadic breast carcinomas. LOH of one or more markers was found in 63% of the tumors. Some had allelic imbalance on a region of 16q which failed to overlap with the LOH in other tumors. We therefore assigned two separate "smallest regions of overlap" to 16q and suggest that this chromosome arm contains at least two different tumor suppressor genes.
Fanconi anaemia (FA) is an autosomal recessive disorder associated with progressive bone-marrow failure, a variety of congenital abnormalities, and predisposition to acute myeloid leukaemia. Cells from FA patients show increased sensitivity to bifunctional DNA crosslinking agents such as diepoxybutane and mitomycin C, with characteristic chromosome breakage. FA is genetically heterogeneous, at least five different complementation groups (FA-A to FA-E) having been described. The gene for group C (FAC) was cloned by functional complementation and mapped to chromosome 9q22.3 (refs 3, 5), but the genes for the other complementation groups have not yet been identified. The group A gene (FAA) has recently been mapped to chromosome 16q24.3 by linkage analysis, and accounts for 60-65% of FA cases. We narrowed the candidate region by linkage and allelic association analysis, and have isolated a gene that is mutated in FA-A patients. The gene encodes a protein of 1,455 amino acids that has no significant homology to any other known proteins, and may therefore represent a new class of genes associated with the prevention or repair of DNA damage.
Summary Loss of heterozygosity (LOH) on chromosome arm 16q occurs in 48-65% of breast tumours. One small region of overlap is located at 1 6q24.3. Two genes located in this region, the cellular adhesion regulatory molecule (CMAR) and the breast basic conserved gene (BBC1), are plausible candidate tumour-suppressor genes. Mutational analysis of the retained copy of these genes has been performed by direct sequencing in a selected set of breast tumours that show LOH at 1 6q24.3 but not at other regions on chromosome arm 1 6q. In CMAR no other alterations than the previously described 4-bp insertion of CACA at nucleotide 241 could be detected, which was also present in constitutional DNA of the same patients. This polymorphism occurs homozygously in germline DNA of normal individuals and breast cancer patients. LOH analysis at this locus shows no preferential loss of a particular variant of the 241 polymorphism. In the BBC1 gene, three different alterations were found, but only one resulted in an amino acid substitution. This is a known polymorphism, however, also appearing in germline DNA. The absence of tumour-specific mutations in CMAR and BBC1 in this selected series of breast tumours implies that another gene at 1 6q24.3 must be the tumour-suppressor gene that is the target for LOH in breast cancer.Keywords: breast cancer; tumour-suppressor gene; chromosome 16; breast basic conserved gene 1; cellular adhesion regulatory molecule Loss of heterozygosity (LOH) on the long arm of chromosome 16 occurs frequently in breast cancer and other tumours. Percentages of LOH in breast cancer vary from 48% to 65% in different regions of 16q in different studies (Cleton-Jansen et al, 1994;Tsuda et al, 1994;Dorion-Bonnet et al, 1995). This suggests the presence of tumour-suppressor genes on this chromosome arm. One of two identified small regions of overlap is located at 16q24.3 between the markers APRT and D16S303 (Cleton-Jansen et al, 1994).Two genes, the cellular adhesion regulatory molecule (CMAR) and the breast basic conserved gene (BBCJ), located in this region are probable candidates for the gene targeted by LOH (Adams et al, 1992;Pullman and Bodmer, 1992;Cleton-Jansen et al, 1995a). The CMAR gene product enhances binding of integrins to extracellular matrix components (Pullman and Bodmer, 1992). A 4-bp insertion of CACA at nucleotide 241 occurs in 38% of Caucasians and in 30% of Japanese (Koyama et al, 1992;Durbin et al, 1994). This 4-bp insertion probably results in an alternative start site for the gene (Durbin et al, 1994).The BBC] gene was identified by differential screening of cDNA libraries of a primary breast carcinoma and of a benign fibroadenoma (Adams et al, 1992). Expression of this gene is higher in fibroadenomas than in carcinomas. The gene is expressed in a great variety of tissues and it is also highly conserved in other species (Bertauche et al, 1994). At the genetic level 85% homology is found with the gene coding for the rat ribosomal protein L13, at the protein level 97% homology is found (Olvera et...
The recently identified Fanconi anaemia A ( FAA ) gene is located on chromosomal band 16q24.3 within a region that has been frequently reported to show loss of heterozygosity (LOH) in breast cancer. FAA mutation analysis of 19 breast tumours with specific LOH at 16q24.3 was performed. Single-stranded conformational polymorphism (SSCP) analysis on cDNA and genomic DNA, and Southern blotting failed to identify any tumour-specific mutations. Five polymorphisms were identified, but frequencies of occurrence did not deviate from those in a normal control population. Therefore, the FAA gene is not the gene targeted by LOH at 16q24.3 in breast cancer. Another tumour suppressor gene in this chromosomal region remains to be identified. © 1999 Cancer Research Campaign
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