Abstract
BackgroundLong-term prognostic significance of loss of heterozygosity on chromosome 9p21 for localized renal cell carcinoma following surgery remains unreported. The study assessed the frequency of deletions of different loci of chromosome 9p along with immunohistochemical profile of proteins in surgically resected renal cancer tissue and correlated this with long-term outcomes.MethodsDNA was extracted from renal tumours and corresponding normal kidney tissues in prospectively collected samples of 108 patients who underwent surgical resection for clinically localized disease between January 2001 and December 2005, providing a minimum of 9 years follow-up for each participant. After checking quality of DNA, amplified by PCR, loss of heterozygosity (LOH) on chromosome 9p was assessed using 6 microsatellite markers in 77 clear cell carcinoma. Only 5 of the markers showed LOH (D9S1814, D9S916, D9S974, D9S942, and D9S171). Protein expression of p15(INK4b), p16(INK4a), p14(ARF), CAIX, and adipose related protein (ADFP) were demonstrated by immunostaining in normal and cancer tissues. Loss of heterozygosity for microsatellite analysis was correlated with tumour characteristics, recurrence free, cancer specific, and overall survival, including significance of immunohistochemical profile of protein expressions.ResultsThe main deletion was found at loci telomeric to CDKN2A region at D9S916. There was a significant correlation between frequency of LOH stage (p = 0.005) and metastases (p = 0.006) suggesting a higher LOH for advanced and aggressive renal cell carcinoma. Most commonly observed LOH in the 3 markers: D9S916, D9S974, and D9S942 were associated with poor survival, and were statistically significant on multivariate analysis. Immunohistochemical expression of p14, p15, and p16 proteins were either low or absent in cancer tissue compared to normal.ConclusionsLoss of heterozygosity of p921 chromosome is associated with aggressive tumours, and predicts cancer specific or recurrence free survival on long-term follow-up.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2514-8) contains supplementary material, which is available to authorized users.
Highlights
Long-term prognostic significance of loss of heterozygosity on chromosome 9p21 for localized renal cell carcinoma following surgery remains unreported
A normal tissue specimen is compared with a tumour sample from the same patient, and deoxyribose nucleic acid (DNA) loss is identified if one of the alleles present in the normal specimen is lost in the tumour, a condition termed as loss of heterozygosity (LOH)
Clinicopathological significance of LOH and proteins expression Cases displaying LOH at least in one marker on 9p21 were highly significantly associated with higher risk of Renal Cell Carcinoma (RCC)-specific death compared to cases with no allelic deletion (Fig. 3a-c)
Summary
Long-term prognostic significance of loss of heterozygosity on chromosome 9p21 for localized renal cell carcinoma following surgery remains unreported. Loss of heterozygosity (LOH) at chromosome 3p and inactivation of the von HippelLindau tumor suppressor (VHL) genes are known to have association with ccRCC [1] Several studies, including those of our own group have shown that chromosome 9p has a critical region of loss in renal cell carcinoma [2,3,4,5]. Significance of these molecular genetic events on 9p, in particular, their correlation with the clinical outcomes following treatment are not fully understood. This study, did not report clinical outcomes or immunohistochemical expression of the cohort, clinical implications of their findings remain unknown
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