Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas

Abstract

The constitutive fragile site at chromosomal band 3p14.2, FRA3B, is the most active common fragile site in the human genome. We have localized aphidicolininduced breakpoints to two distinct clusters, separated by 200 Kb, in FRA3B (Paradee et al., 1996). Sequence analysis of these regions identi®ed two polymorphic microsatellite markers immediately adjacent to each of these breakpoint clusters. In this report we have used these two new microsatellites and 14 additional 3p microsatellites to analyse chromosome 3p breakage and loss in 94 sporadic RCC samples, including nonpapillary, papillary and oncocytomas. We have found heterozygous loss of 3p14 sequences in 460% of the RCC samples, including both clear cell and papillary renal cell carcinomas. We have found frequent breakage in the region immediately surrounding FRA3B, demonstrating that FRA3B does play a role in chromosome breakage and loss in RCC. In contrast to other reports, 450% of the papillary tumors also showed LOH of 3p markers. We also observed microsatellite instability (MIN) with most of the tested markers in seven of eight oncocytomas and one of 69 clear cell carcinomas. The MIN in some oncocytomas was of the RER+ (replication error) type I phenotype. None of the ®ve 3p14.2 markers detected any homozygous deletions in tumor samples, but 69/94 (73%) of the tumors had LOH for the region, which includes the recently identi®ed FHIT gene.

Loss of heterozygosity on the long arm of human chromosome 7 in sporadic renal cell carcinomas

“…We have recently shown a clustering of breakpoints in the FRA3B region in pancreatic adenocarcinomas (Shridhar et al, 1996) similar to the observations reported here. We also observed a dramatic clustering of breakpoints in 3p14.2 with frequent multiple interstitial deletions in RCCs (Shridhar et al, 1997). It will be interesting to see if a similar phenomena is also true for FRA7G in various types of cancers.…”

“…There was no correlation between tumor grade (not listed) or cell type and 7q LOH, MIN, or ampli®cation in renal cell carcinomas. (Shridhar et al, 1997;Cohen et al, 1979;Wang et al, 1984). It is widely accepted that alterations on this chromosome are probably the initiating events in the development of RCC.…”

“…The biological signi®cance of at least some fragile sites is that they might predispose chromosomes to breakage which would then result in translocations, deletions, or even ampli®cations that could play a role in tumor development. For example, we have demonstrated that a high percentage of both pancreatic adenocarcinomas (Shridhar et al, 1996) and sporadic RCCs (Shridhar et al, 1997) have breakpoints in FRA3B, the most common fragile site in the human genome.…”

Mutations in the arginine-rich protein gene (ARP) in pancreatic cancer

“…Although this gene showed no gross structural alterations in any sporadic renal cell carcinomas (RCC) or lung tumors, we found a specific mutation involving codon 50 in 10/21 renal tumors, 5/ 13 prostate tumors, 6/18 NSCLC samples, 9/22 breast tumors, and 5/21 head and neck carcinomas. (Shridhar et al, 1996(Shridhar et al, , 1996a. The presence of this speci®c mutation in a variety of tumor types, and in one third of all tumors studied, suggests that this mutation is causal in these tumors, and has led us to analyse other cancers including pancreatic adenocarcinomas for corresponding mutations.…”

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

“…This gene contains an imperfect trinucleotide repeat which encodes a string of arginines. A specific mutation (ATG50?AGG) within this region was detected in 10/ 21 RCC, 8/20 lung cancers (NSCLC and SCLC) and other solid tumors (Shridhar et al, 1996a(Shridhar et al, ,b, 1997. Rare mutations in other codons were also found.…”