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Aims:

EMAST affecting several tumor types (e.g. bladder, lung and skin cancers) are a new type of microsatellite alterations distinct from the microsatellite instability (MSI) phenotype in hereditary nonpolyposis colorectal cancer (HNPCC)-related tumors. To date, this phenomenon, which was suggested to be connected with defects in p53-dependent repair mechanisms, has not been examined in RCC and was the subject of our study.

Methods:

We analyzed 162 RCC tumors of different subtypes for MSI using the national cancer institute consensus panel for HNPCC detection plus BAT40, and additional 10 markers frequently detecting EMAST in other cancer types. We also assessed p53 gene alterations (loss of heterozygosity (LOH, TP53alu)) and expression of p53 and mismatch repair (MMR) genes (hMLH1, hMSH2) by immunohistochemistry (IHC) on tissue micro arrays. Scoring was performed as follows: p53: strong nuclear staining in at least 10% of cells was regarded as positivity; MMR proteins: negative, no stained nuclei; weak, ≤ 20% of nuclei were stained; moderate, ≤ 50% of nuclei were stained; strong, > 50% of nuclei were stained. The obtained results were tested for possible associations to histopathological characteristics by applying contingency table analyses (Fisher’s exact test). P values of less than 0.05 were considered to be significant.

Results:

MSI was found in 2.0% (3/152) of analyzable cases. EMAST was detected in 0.6% (1/162) and LOH in the investigated markers in 19.8% (32/162). These LOH were significantly more abundant in clear cell (cc) and papillary (pap) RCC than in chromophobe (cp) RCC (p = 0.021). LOH in p53 could be demonstrated in 3.1% (3/97) of informative tumors. IHC revealed p53 positivity in 8.5% (12/142) of cases. We did not find any correlations to histopathological characteristics. hMLH1 expression was reduced (negative or weak) in 84.4% (119/141) of cases. Among them, ccRCC displayed a significantly higher loss of hMLH1 than pap and cpRCC (p < 0.001). hMSH2 expression was decreased (negative or weak) in 51.2% (65/127) of tumors, whereas cpRCC showed significantly less reduction than cc and papRCC ( p< 0.001). Loss of both MMR proteins was detected in 50.0% (63/126) of tumors, again significantly less frequent in cpRCC (8.3%, p < 0.001). Combined loss of both proteins occurred in 55.3% (42/76) of ccRCC and 53.8% (14/26) of papRCC.

Conclusions:

This first study examining MSI and EMAST in a large series of RCC demonstrated that both types of genetic instability are rare events in RCC, although large fractions of ccRCC and papRCC have impaired MMR expression. p53 overexpression is infrequent and fits the small number of p53 LOH. Therefore, EMAST does not play an important role in RCC development. Remarkable is the connection of diminished MMR protein expression and tumor entity, which might contribute to the different biological behavior of RCC subtypes.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA