RBSP3 is frequently altered in premalignant cervical lesions: clinical and prognostic significance.
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.
Mitra
Sraboni
S
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
Mazumder Indra
Dipanjana
D
Bhattacharya
Nilanjana
N
Singh
Ratnesh K
RK
Basu
Partha S
PS
Mondal
Ranajit K
RK
Roy
Anup
A
Zabarovsky
Eugene R
ER
Roychoudhury
Susanta
S
Panda
Chinmay K
CK
D000328:Adult; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D002893:Chromosomes, Human, Pair 3; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
C486483:CTDSPL protein, human; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins