Detection of loss of heterozygosity at RAD51, RAD52, RAD54 and BRCA1 and BRCA2 loci in breast cancer: pathological correlations

Abstract

Summary Loss of heterozygosity (LOH) in loci of the 15q15.1, 12p13, 1p32, 17q21 and 13q12-13 regions may collaborate in the inactivatio n of RAD51, RAD52, RAD54, BRCA1, BRCA2 and possibly other genes implicated in the repair of double-stranded DNA and in DNA recombination. We investigate allelic losses in microsatellites of the RAD51, RAD52, RAD54, BRCA1 and BRCA2 regions, and their correlations with nine pathologic parameters in 127 breast carcinomas. The LOH analysis was performed by amplifying DNA by PCR, using 15 markers of the 15q15.1, 12p13.3, 1p32, 17q21 and 13q12-13 regions. LOH was found in the RAD51 region in 32% of tumours, in t he RAD52 region in 16%, in RAD54 in 20% and in the BRCA1 and BRCA2 regions in 49% and 44% respectivel y. Significant correlations between one or more regions with concomitant LOH and pathologic parameters were observed with respect to age (P = 0.008), oestrogen receptor content (P = 0.03), progesterone receptors (P = 0.003), higher grade (P = 0.001), more advanced stage (P = 0.004) and peritumoural vessel involvement (P < 0.0001). The number of cases in which LOH was observed simultaneously in two or more regions was always higher than expected on the basis of their statistical probabilit y, and curiousl y, the three patients with LOH at five regions concomi tantly were under the age of 30 years. These results suggest that LOH at these regions could be related to breast cance r, and probably to a poo r tumour prognosis .

Sporadic breast cancer in young women: Prevalence of loss of heterozygosity at p53, BRCA1 and BRCA2

“…These frequencies are higher than those reported previously at BRCA1 and BRCA2 for unselected series of breast cancers. [12][13][14][15][16][17][18][19] Moreover, the high LOH detected at D17S855 (64.5%) and D13S260 (74.2%) in cancers from young women was significantly higher than the 35.5% and 30.0% LOH noted for D17S855 and D13S260 in cancers from women aged 55-72 years (p Ͻ 0.025 and p Ͻ 0.005 respectively). MSI was rare and was found at only a single marker for 4 of the cases from women aged 26 -35 years and 4 of the cases from women aged 55-72 years.…”

“…15,19 A high rate of allelic loss at the 3 chromosomal regions relating to BRCA1, BRCA2 and p53 has been associated with features in breast cancer that are linked to more aggressive clinical behaviour, such as large size, high grade and lack of oestrogen receptors. 12,14,19 In view of the high incidence of these clinicopathologic features in breast cancers from young women, our study investigated the frequency of LOH at chromosomes 17q21 (BRCA1), 13q12-13 (BRCA2) and 17p13 (p53), using 10 different polymorphic microsatellite markers, in a series of sporadic cancers from women with a cutoff age at diagnosis of 35 years. The findings were compared with those for a group of sporadic symptomatic cancers from women aged 55-72 years that had been matched for size, grade and node status, to determine whether any relationships found related to age and/or tumour characteristics.…”

“…11 LOH of the region on the long arm of chromosome 17, which includes BRCA1, has been found in sporadic breast cancer at frequencies ranging from 20 to 63%. [12][13][14][15][16] Similarly, mutations in the BRCA2 gene are rare in sporadic breast cancer, 17 but LOH in chromosome 13q12 region has been reported in 20 -54% of sporadic cases. 12,14,15,18 The p53 gene is located on the short arm of chromosome 17 and this region also shows a high frequency of LOH in breast cancer.…”

“…[12][13][14][15][16] Similarly, mutations in the BRCA2 gene are rare in sporadic breast cancer, 17 but LOH in chromosome 13q12 region has been reported in 20 -54% of sporadic cases. 12,14,15,18 The p53 gene is located on the short arm of chromosome 17 and this region also shows a high frequency of LOH in breast cancer. 15,19 A high rate of allelic loss at the 3 chromosomal regions relating to BRCA1, BRCA2 and p53 has been associated with features in breast cancer that are linked to more aggressive clinical behaviour, such as large size, high grade and lack of oestrogen receptors.…”

Genetic instability in the RAD51 and BRCA1 regions in breast cancer

“…Loss of heterozygosity in the genomic region 15q14-q21, containing RAD51, has been reported in 32-70% of breast cancer cases [55][56][57], 56% of lung cancer [55], 67% of colorectal cancer [55], 46-54% of malignant mesothelioma [58,59], and 39% of bladder transitional cell carcinoma [60]. LOH at 17q21 has been revealed in about 30-60% of breast [61,62], ovarian [63] and colorectal [64] cancer cases.…”