Microsatellite instability and loss of heterozygosity in mammary carcinoma and its probable precursors

Abstract

Summary Microsatellite instability is a form of genetic damage that may be due to defective mismatch repair genes and may be a marker of processes leading to malignancy. We have analysed a series of epithelial hyperplasia of usual type, carcinomas in situ and invasive and metastatic carcinomas from the mammary gland on the assumption that they represent stages in the evolution of mammary carcinoma. Eight markers on chromosomes 3p, 4q, 9p, 11p, 14q, 17p, 17q and Xq were examined for microsatellite instability and loss of heterozygosity. High rates of loss on chromosomes 17p, 17q and Xq indicate that these chromosomal arms contain genes important in mammary carcinogenesis. The rate of microsatellite instability observed in this study was uniformly low, irrespective of the lesion. This implies that microsatellite instability is not a marker of malignancy in most instances of mammary neoplasia.

Microsatellite instability in medullary breast carcinomas

“…Therefore, in contrast with the association described between the presence of a prominent lymphoid infiltration and genomic instability in gastro-intestinal carcinomas, no such association was found in breast carcinomas. The percentage of MBCs with MSI in our series fits with that previously reported for breast carcinomas in general, which varies from 5% to 21% (Yee et al, 1994;Dillon et al, 1997;Marchis et al, 1997). Marchis et al (1997) did not find any association between lymphoid infiltration and MSI in non-medullary breast carcinomas.…”

“…Dillon et al (1997) reported that in breast cancer the type of markers involved in instability are mainly of tri-and tetranucleotide repeats, suggesting that the molecular basis of instability in breast cancer is different from what is observed in colon cancer or that the instability observed in the breast is a secondary genetic event occurring during progression. Dillon et al (1997) showed that MSI is present in ductal hyperplasias, carcinomas in situ and invasive carcinomas but that the rate of instability remains similar in the 3 types of lesion. The absence of MSI observed by us within this type of nucleotide repeat does not support this hypothesis, though only 5 cases were analysed.…”

“…We also searched for instability in the repeat sequences of TGF-␤ RII and BAX genes in 19 cases for which DNA was available from tumours and normal control tissues. We also searched for MSI in 5 of the MBC cases, in which both tumour and normal tissue DNA were available, using markers located in several loci and with different types of tandem repeat sequence: 1 dinucleotide (CA) repeat (D1S158), 8 tetranucleotide repeat sequences (D3S1358, D5S818, D7S820, D8S1179, D13S317, D21S11, FGA and VWA) and 1 pentanucleotide repeat (dAAAAT), localized in p53 intron 1, since several studies have suggested that a different pattern of MSI, exhibiting a higher number of tandem repeated nucleotides, might occur in breast cancer (Dillon et al, 1997). We also determined the proliferation index of the tumours and searched for associations between proliferation rate and RER status, to check whether tumours with MSI would harbour differences in growth rate.…”

Genetic Heterogeneity in Ductal Carcinoma of the Breast

“…Thus, these examples most likely represent a "baseline" level of instability rather than the RERϩ phenotype described in colon cancer. These observations are compatible with most reports in the literature, which find some sporadic MSI in microdissected breast cancer, but do not find the high frequency MSI observed in colon cancers with the RERϩ phenotype (Aldaz et al, 1995;Contegiacomo et al, 1995;Dillon et al, 1997;Formantici et al, 1999;Fujii et al, 1998;Gorgoulis et al, 1998;Kasami et al, 1997;Paulson et al, 1996;Rush et al, 1997;Shaw et al, 1996;Sourvinos et al, 1997;Tomita et al, 1999;Toyama et al, 1996;Walsh et al, 1998;Wooster et al, 1994;Yee et al, 1994). One recent study (Anbazhagan et al, 1999) reported no examples of sporadic MSI in a large panel of breast cancers and other studies have observed MSI only rarely (Ͻ5% of cases) (Huiping et al, 1999;Jonsson et al, 1995).…”

"Estudo das alterações dos microssatélites D6S251 e D6S252 no carcinoma basocelular esporádico"

“…A incidência reportada em alguns estudos varia de 0 a 30% embora, menos de 10% apresentem altas taxas de MSI 36,37 . Mais adiante discutiremos mais acerca da instabilidade genômica que ocorre no CCNM, em especial no CBC.…”