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

Abstract

Previous studies have shown that breast cancers have more aggressive pathologic features in young women. In order to examine genetic alterations associated with earlyonset breast cancer, 31 patients with no known family history, aged 26 -35 years at diagnosis, were examined for loss of heterozygosity (LOH) at 3 key chromosomal intervals: 17p (p53), 17q 21 (BRCA1) and 13q12-13 (BRCA2) using polymerase chain reaction analysis of polymorphic microsatellite markers. These were compared with 31 patients aged 55-72 years that were matched for size, type and grade. All young breast cancer cases exhibited LOH for at least 1 marker and 20 cases (64.5%) exhibited LOH at 1 or more markers from each interval. Although the incidence of breast cancer in younger women is low, with the Surveillance, Epidemiology and End Results (SEER) programme in the United States finding that only 6.5% of breast cancers occur by the age of 40 years, 1 there is evidence from several studies that it is biologically different. Carcinomas occurring in women under 35 years have a significantly higher chance of being grade III (poorly differentiated), lacking steroid receptors and having high proliferation rates. [2][3][4][5] The poorer prognosis reported for this age group may be related to the biologic nature of the tumours. 6 -9 A higher frequency of stabilised p53 protein, as detected by immunohistochemistry, has been demonstrated in breast cancers from women younger than 35 years, but more detailed molecular characterisation is required that could provide insight into the different biologic and behavioural features of breast cancers in this young age group. One approach that can be used is loss of heterozygosity (LOH) analysis of key chromosomal regions that have been implicated in breast cancer.Germline mutations in the BRCA1 gene account for approximately 45% of inherited breast cancers. 10 Although somatic mutation of BRCA1 has not been found, BRCA1 protein expression is reduced in about 30% of sporadic breast carcinomas. 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. 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 spora...

Identification of a Novel Tumor Suppressor Gene p34 on Human Chromosome 6q25.1

“…Hence, one strategy was to look for genes in the 6q23-25 by analyzing LOH patterns in sporadic tumors. For example, human chromosomal region 17q21, which harbors the familial breast cancer susceptibility gene BRCA1, frequently shows LOH in tumors of sporadic and familial breast cancer patients (9,10). Sporadic and familial colon cancer patients also frequently show LOH in chromosomal region 5q21, where the familial adenomatous polyposis susceptibility gene, APC, is located (11).…”

Mapping loss of heterozygosity in normal human breast cells from BRCA1/2 carriers

“…Loss of the wild-type BRCA1 or BRCA2 allele has been shown in breast tumours arising in patients carrying a germline mutation in one of these genes Cornelis et al, 1995;Merajver et al, 1995;Osorio et al, 2002) and in some sporadic breast tumours (Hanby et al, 2000;Katsama et al, 2000;Johnson et al, 2002). The loss of the wild-type allele is presumed to be one of the first genetic events leading to tumour formation in familial breast cancer cases (Cornelis et al, 1995).…”

Cloning of a New Gene/s in Chromosome 17p3.2-p13.1 that Control Apoptosis

“…Loss of genetic material (LOH) in the chromosome 17 pl3.2 at the micro satellite marker D17S796 has been identified in hepatocellular carcinoma (54), atypical ductal hyperplasia and in situ ductal carcinoma of breast (39,55). Our results shown LOH at the same region in MCF-IOF cells treated with the chemical carcinogen benz(a)pyrene (BP).…”