RBSP3 is frequently altered in premalignant cervical lesions: Clinical and prognostic significance

Abstract

To understand the importance of frequent deletion of 3p22.3 in cervical carcinogenesis, alterations (deletion/methylation/expression) of the candidate genes STAC, MLH1, ITGA9, and RBSP3, located in the region, were analyzed in 24 cervical intraepithelial neoplasia (CIN) and 137 uterine cervical carcinoma (CACX) samples. In CIN, RBSP3 deletion (48%) and methylation (26%) were high compared with the other genes (4-9%). In CACX, alterations of these genes were as follows: deletion: STAC (54%) > MLH1 (46%) > RBSP3 (45%) > ITGA9 (41%), methylation: RBSP3 (25%) > ITGA9 (24%) > STAC (19%) > MLH1 (13%). Overall, alterations of RBSP3 showed association with CIN, whereas for STAC and MLH1, this frequency increased significantly from CIN --> Stage I/II and for ITGA9 from CIN --> Stage I/II and also from Stage I/II --> Stage III/IV. Quantitative mRNA expression analysis showed differential reduced expression of these genes in CACX concordant to their molecular alterations. The more active RBSP3B splice variant was underexpressed in CACX. RB1 was infrequently deleted in CACX. Concordance was seen between (i) inactivation of RBSP3 and intense p-RB1 nuclear immunostaining and (ii) low/absence of MLH1 expression and its molecular alterations in CACX. In normal cervical epithelium, p-RB1 immunostaining was low in differentiated cells, whereas MLH1 staining was seen in both nucleus and cytoplasm irrespective of differentiation stage. Alterations of the genes were significantly associated with poor prognosis. High parity (>or=5)/early sexual debut (<or=19 years) coupled with RBSP3 alterations/RB1 deletion predicted worst prognosis. Thus, inactivation of RBSP3 might be one of the early events in cervical carcinogenesis.

Novel tumor suppressor candidates on chromosome 3 revealed by NotI-microarrays in cervical cancer

“…High frequencies (53-89%) of down-regulation of all these genes were revealed for the first time in cervical SCC excepting RBSP3. 23,24 Along with known TSGs, RASSF1A, RBSP3 and ITGA9 (see Table S2), two poorly studied genes, APRG1 and VILL, were strongly down-regulated in 60% and 53% of cervical tumors respectively. There is only scarce information about their functions and involvement in cancer.…”

Integrin alpha9 (ITGA9) expression and epigenetic silencing in human breast tumors

“…From the other side, extensive search of genetic/epigenetic aberrations of ITGA9 by NotI-micorarray identified frequent (more than in 30%) aberrations (deletions, methylation) in kidney, lung, breast, ovary, cervical, prostate and colorectal cancer, 33,34 in 45-55% of head and neck squamous cell carcinomas 35 and 65% of uterine cervical carcinomas (41% deletion and 24% methylation). 36 A possibility of ITGA9 CpG-island methylation was verified in cervical 33 and colorectal 34 tumors by methylspecific PCR and bisulfite sequencing.…”

CTDSPL (CTD (Carboxy-Terminal Domain, RNA Polymerase II, Polypeptide A) Small Phosphatase-Like)

“…-Reduced mRNA expression was seen in CACX (Mitra et al, 2010). -RBSP3B (larger, active isoform) was underexpressed in CACX (Mitra et al, 2010).…”

“…-Reduced mRNA expression was seen in CACX (Mitra et al, 2010). -RBSP3B (larger, active isoform) was underexpressed in CACX (Mitra et al, 2010). -In HPV infected cervical cancer, high deletion (42% cases) was observed, with significant variation (p<0.05) between metastatic (64%) and non-metastatic (32%) cases (Anedchenko et al, 2007) -Altogether, copy number change was seen in 51% cases (Anedchenko et al, 2007).…”

“…Note -High deletion (48%, 45% cases) and methylation (26%, 25% cases) was seen in CIN and CACX respectively (Mitra et al, 2010). -Reduced mRNA expression was seen in CACX (Mitra et al, 2010).…”