not yet recognized, and the usual mutations associated with MSI in hereditary EC are not found in the sporadic cancers (29,30). It is postulated that there may be epigenetic inacti-vation of MSH1 in sporadic cases, which might not be evident in the usual mutational screens used to query the functional integrity of MLH1 (10,30,31).
The manner in which MSI influences cell function is extremely complex, and beyond the scope of this chapter. Suffice to say that secondary inactivation of the specific genes may occur by alteration of repeat sequences in the coding regions, epigenetic inactiva-tion of MSI in the regulatory domains, or a hypermutable state in the nonrepeat regions. The overall effect may not be mediated through PTEN or p53 inhibition, as these genes are comparable in both stable and MSI-positive cancers (10,30,31).
MSI is a well-known feature of MMR-driven tumorigenesis of uterine mucosa in sporadic tumors, which show predominantly somatic hypermethylation of MLH1 (32). The finding of MSI in endometrial hyperplasia and altered protein staining for the MMR genes suggest that inactivation of MMR genes is an early event in endometrial carcinogenesis.
In the general population, MSI is typically seen more frequently in type I endometri-oid carcinomas (17-29%) compared with serous papillary types (5-8%) (20), and MSI was seen more frequently in the tumors of patients younger than 50 years age. This is consistent with younger average age of diagnosis for HNPCC-related ECs. However, the presence or absence of MSI did not correlate with clinical stage or overall prognosis of these tumors (33). Immunoperoxidase staining for MMR genes in HNPCC-related EC tissues showed strong positivity in the tumor foci, but not in the adjacent normal tissues, suggesting a possible clonal population of the malignant cells (34). Interestingly, MLH1 and MSH2 protein losses have been demonstrated in the benign endometrial hyper-plasias of HNPCC-related cancer patients, but similar changes were not seen in the endometrial hyperplasias of sporadic cases (35). This may characterize an early event in the pathway of the endometrial carcinogenesis in the HNPCC syndrome patients, and might possibly serve as a helpful marker for early diagnosis of these malignancies (35). To date, not much information is available regarding the prognostic significance of MSI. Although, one study (36) suggests an association of MSI-positive phenotype with higher Fédération International de Gynécologic et d'Obstetrique (FIGO) clinical stage and histological grade, and with mucinous and cribiform patterns, and increased necrosis in the tumors.
de Leeuw et al. (32) studied MSI, which has been observed in CRC and in certain extracolonic malignancies, particularly EC, in the Lynch syndrome. In the study of all EC (n = 12) from patients with MLH1 and MSH2 germline mutations, de Leeuw et al. observed MSI-high phenotype to involve all types of repeat markers. However, in EC from MSH6 mutation carriers, only 36% (4 out of 11) demonstrated an MSI-high phenotype. MSI-high phenotype was observed in endometrial hyperplasias from MSH2 mutation carriers, whereas hyperplasias from MLH1 mutation carriers exhibited an MSI-stable phenotype. Instability of only the mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers in 29 out of 31 (94%) endometrial tumor foci. Correlation found between the variation in the extent and level of MSI and the age of onset of EC suggested differences in the rate of progression. A high frequency of MSI in endometrial hyperplasias was found only in MSH2 mutation carriers, and might indicate more rapid tumor progression in these patients. de Leeuw et al. concluded that assessment of altered MLH1, MSH2, and MSH6 protein staining combined with MSI analysis can direct the mutation analysis to predict the MMR germline mutation in endometrial tumors.
On the other hand, Ichikawa et al. (34) analyzed MSI as well as the immunohisto-chemical expression of MLH1 and MSH2 proteins, in 20 histologically normal epithe-lia (12 endometrial and 8 ovarian) and 8 cancers (four endometrial and four ovarian) from 20 individuals who were part of seven unrelated Lynch syndrome families. MSI was observed in endometrial (75%) and ovarian (100%) cancers. However, these investigators did not find a single case that exhibited MSI in histologically normal epithelia of the endometrium or ovary. In their investigation of immunohistochemical expressions of MLH1 and MSH2 proteins in histologically normal epithelia, they found no genetic changes predisposing to malignancy. However, in cancer cases there was a correlation between the expression of MLH1 and MSH2 proteins, the presence of germline mutations in MLH1 and MSH2 genes, and the presence of MSI in the tumor. These authors concluded that MSI expression and expression of MLH1 and MSH2 proteins are biomarkers, which have no efficacy for the early detection of endometrial and ovarian malignancy in cancer-unaffected HNPCC germline mutation carriers.
Planck et al. (37) investigated MSI-high phenotype and MMR protein expression in a series of patients harboring both EC and CRC. Their findings indicated that double primary malignancies of the colorectum and endometrium at a young age (<50 years)
raised the index of suspicion for the Lynch syndrome. Shannon et al. (8), noted that MSI occurs in 17-32% of sporadic ECs and in 3-17% of sporadic ovarian cancers. He hypothesized that a higher rate of MSI might be found in primary carcinomas of the ovary and the endometrium, which occurred in women with synchronous primary cancers of these organs. However, based on 52 cases of synchronous tumors of the ovary and endometrium from the databases of four gynecological oncology units, Shannon et al. (8) failed to identify MSI-high in this cohort. This led the authors to conclude that synchronous primary ovarian and endometrial carcinomas are unlikely to be part of the HNPCC syndrome unless the family history is compatible with the modified Amsterdam criteria.
Noting that CRC and EC are the two most common cancers in Lynch syndrome, Schwartz et al. (38) reported that MSI-positive EC in Lynch syndrome shows mutations in some of the same genes as does the CRC pathway, including BAX (55%), MSH3 (28%), andMSH6 (17%). They also detected frameshift mutations in caspase-5, a member of the caspase family of proteases that has a (A)10 repeat within its coding region, in MSI-positive tumors of the endometrium (28%), colon (62%), and stomach (44%). They suggested from these observations that caspase-5 is a target gene in the MSI pathway to cancer.
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