Microsatellite instability differences between familial and sporadic ovarian cancers

Abstract

DNA instability, reflected in altered patterns of short tandem repeat sequences (microsatellites) in dividing cells, has been described in hereditary non-polyposis colon cancer (HNPCC) and in other tumor types. Ovarian cancer (OC), although most often a sporadic cancer, can recur, with HNPCC, as part of the Lynch cancer family syndrome. In an investigation of microsatellite instability (MIN) in 90 OC cases, we found MIN in 3/28 (11%) OC cases with, and 8/62 (13%) without, a family history of cancer. For 2/3 MIN+ OC cases with family cancer history consistent with the Lynch cancer family syndrome, we found additional bands in the microsatellite patterns in tumor versus normal tissue (HNPCC-type of MIN), but no germline mutations in two DNA mismatch repair genes, hMSH2 and hMLH1. In 7/8 MIN+ sporadic OC cases distinct MIN patterns not commonly reported in HNPCC were found. These are characterized by partial or total band shifting, leading to fewer bands and/or changes in the intensity of individual bands restricted to the tumor. In only one case was a germline change in hMSH2 or hMLH1 identified: this was subsequently found to be a polymorphism. An apparent hMLH1 somatic change confined to the tumor was found in another case. The fact that we found no germline pathologic mutations in hMSH2 and hMLH1 (predominant sites of mutation in HNPCC) in MIN+ OC cases, suggests that the genetic basis of MIN in OC can be different from that in HNPCC; our finding that distinct microsatellite banding patterns largely distinguish sporadic from familial OC, may reflect the involvement of different DNA repair genes in MIN in individual OC cases.

hMSH2 and GTBP expression in advanced stage epithelial ovarian cancer

“…We demonstrated that hMSH2 protein is exclusively localized in the nuclear compartment and is expressed in the vast majority of neoplastic cells from primary ovarian tumours. These results are consistent with those of Brown et al (1997), and with previous demonstrations that microsatellite instability occurs with a low prevalence in advanced stage ovarian cancer (King et al, 1995;Arzimanoglou et al, 1996), indicating that the majority of tumour cells from these patients carry a functional hMSH2 genes. Western blotting analysis revealed that hMSH2 and GTBP display a wide range of expression levels, suggesting that both these proteins could play a role in the biology of ovarian tumour cells.…”

Microsatellite instability in European hepatocellular carcinoma

“…Instability at widespread highly polymorphic tandem repeat DNA sequences, known as microsatellites, has been reported in hereditary nonpolyposis colorectal cancer (HNPCC; Thibodeau et al, 1993), as well as in a number of other familial and sporadic cancers including colon (Ionov et al, 1993), endometrium (Duggan et al, 1994), oesophagus , stomach (Rhyu et al, 1994), pancreas (Brentnall et al, 1995), lung (Shridhar et al, 1994;Merlo et al, 1994), bladder (Gonzalez-Zulueta et al, 1993), kidney , breast (Paulson et al, 1996), ovary (Arzimanoglou et al, 1996), brain (Zhu et al, 1996) and haematopoietic system Kaneka et al, 1996), and some preneoplastic or in¯ammatory tissues (Brentnall et al, 1995(Brentnall et al, , 1996Salvucci et al, 1996). In sporadic tumours, the extension and the type of microsatellite alterations is generally less pronounced than in HNPCC patients and often appears as one or few additional alleles at only one or few loci (Wooster et al, 1994).…”

A change in microsatellite instability caused by cisplatin-based chemotherapy of ovarian cancer

“…In primary epithelial ovarian cancer, the percentage of tumours positive for MSI has been reported to be no more than 12% (Arzimanoglou et al, 1996) to 26% (Codegoni et al, 1999), and even in ovarian cancers without MSI, it is uncommon to experience little or no tumour reduction with CDDP treatment. Therefore, it is difficult to predict a tumour's resistance to CDDP solely by the presence or absence of MSI in the primary tumour.…”