VHL and FHIT locus loss of heterozygosity is common in all renal cancer morphotypes but differs in pattern and prognostic significance

Deletions involving 3p are believed to be typical for conventional (clear c ell) renal cell carcinoma (cRCC), with confirmed and suspected targets bein g the VHL and FHIT tumor suppressor genes, respectively. By contrast, 3p de letions are felt to be rare in papillary RCC (pRCC) and chromophobe RCC (ch RCC); however, this belief is based on relatively scant data. In particular , 3p14.2 deletions, possibly resulting in FHIT inactivation, have been rare ly studied in pRCC or chRCC even though they may be relevant in early renal tumorigenesis, We therefore examined 3p deletion rates and patterns in pRC C and chRCC with particular attention to 3p14.2. We examined 16 chRCCs and 27 pRCCs for loss of heterozygosity (LOH) at 3p25-26 and 3p14.2 using 13 we ll-mapped microsatellite markers. Those pRCC with LOH at 3p25-26 were also screened for VHL gene mutations. The results were correlated with tumor his tology and patient outcome and compared with data we had obtained previousl y on cRCC. We found similar overall 3p LOH rates in pRCC (59%), chRCC (86.6 %), and cRCC (75.8%). In pRCC and chRCC, LOH at 3p25-26 was more common tha n at 3p14.2, whereas the converse was true for cRCC, In the pRCC with 3p25- 26 LOH, we confirmed that this was not associated with mutations of the VHL gene. At 3p14.2, LOH rates of pRCC were lower than those of cRCC and chRCC (p < 0.02). All morphotypes showed a predominately interstitial LOH patter n, which was most pronounced in the 3p14.2 region in cRCC, 3p LOH in chRCC was associated with improved patient outcome, mirroring our previous cRCC d ata. We conclude that 3p LOH is a universal phenomenon in RCC, but has diff erent underlying mechanisms, molecular targets, and implications in the dif ferent morphotypes, although FHIT inactivation may play a role in both cRCC and chRCC tumorigenesis.