Purpose: The human ortholog of Rabphillin-3A-Like gene (RPH3AL) is located at 17p13.3 distal to the p53 gene locus (17p13.1). In our previous study, we observed one third of sporadic colorectal adenocarcinomas (CRCs) exhibited loss of heterozygosity (LOH) at these loci. The current study assessed whether these molecular abnormalities are associated with patient race and their clinical outcomes.
Methods: One hundred thirty-seven archival tissues of CRCs (80 non-Hispanic Caucasians and 57 African-Americans), with long follow up information, were selected for this study. The LOH status of these two loci was assessed by evaluating four polymorphic microsatellite markers spanning the RPH3AL locus (D17S1866, D17S926, D17S849 and D17S643) and two polymorphic microsatellite markers of the p53 locus (TP53.PCR15 and TP53.PCR18) using ABI 3100 genetic analyzer. Also, we stained 103 (out of 137 cases) tissue sections to assess the phenotypic expression of RPH3AL and p53 using anti-human RPH3AL polyclonal (dilution: 10ug/ml; GenScript, Piscataway, NJ) and anti-human p53 monoclonal (Clone: BP53.12.1 and dilution: 1:80; BioGenex, San Ramon, CA) antibodies. The immunostained slides were evaluated by two independent pathologists.
Result: Our analysis demonstrated that 50% of African-Americans have exhibited LOH at 17p13.1 (25 of 50 informative cases) and 65% cases (36 of 55 informative cases) were positive for LOH at 17p13.3 locus. In non-Hispanic Caucasians, the incidence of LOH at p53 locus was 58% (40 of 69 informative cases) and the LOH incidence at RPH3AL locus was 74% (58 of 78 informative cases). In African-Americans, 42% CRCs (21 of 50 informative cases) have exhibited LOH at both loci and 26% CRCs (13 of 50 informative cases) were without LOH at these two loci. In non-Hispanic Caucasians, 51% (35 of 69 informative cases) cases were positive for LOH at both these loci and 14% (10 of 69 informative cases) cases were without LOH at these two loci. Among the 21 cases which exhibited LOH at both loci in African-Americans, 12 cases had nodal metastasis (57%), whereas only 23% (3 of 12 cases) had nodal metastasis in CRCs without LOH at these two loci. Such a difference was not observed in non-Hispanic Caucasians (46% nodal metastasis in CRCs with LOH at both loci versus 40% nodal metastasis in CRCs without LOH at these two loci). In African-Americans, there was a significant difference in survival between cases with and without LOH at both loci (logrank, p=0.044). This difference was not observed in non-Hispanic Caucasians (logrank, p=0.750). In this study, we did not find a significant correlation between immunohistochemical expression of p53 and RPH3AL with their underlying genetic abnormalities at these two loci.
Conclusion: These findings suggest that there is a significant correlation between LOH at p53 and RPH3AL loci and the aggressive tumor behavior in African-Americans; thus, contributing for their short survival. This work is supported partially by funds from the Department of Pathology, University of Alabama at Birmingham and by a grant from the National Institute of Health/National Cancer Institute (RO1-CA98932-01).
- American Association for Cancer Research