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Frequent Alterations of the Candidate Genes hMLH1, ITGA9 and RBSP3 in early Dysplastic Lesions of Head and Neck: Clinical and Prognostic Significance

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Title Frequent Alterations of the Candidate Genes hMLH1,
ITGA9 and RBSP3 in early Dysplastic Lesions of Head
and Neck: Clinical and Prognostic Significance
 
Creator Ghosh, Amlan
Ghosh, Susmita
Maiti, Guru Prasad
sabbir, Mohd.Golam
Zabarovsky, Eugene R
Roy, Anup
Roychoudhury, Susanta
Panda, Chinmay Kumar
 
Subject Molecular & Human Genetics
 
Description To understand the association between candidate tumor suppressor
genes (TSGs) human mismatch repair protein homologue
1 (hMLH1), AP20 region gene 1 (APRG1), integrin a RLC (ITGA9),
RB1 serine phosphates from human chromosome 3 (RBSP3) at chromosomal
3p22.3 region and development of head and neck
squamous cell carcinoma (HNSCC), alterations (deletion ⁄ promoter
methylation ⁄ expression) of these genes were analyzed in 65 dysplastic
lesions and 84 HNSCC samples. Clinicopathological correlations
were made with alterations of the genes. In HNSCC, deletion
frequencies of hMLH1, ITGA9, and RBSP3 were comparatively
higher than APRG1. Overall alterations (deletion ⁄ methylation) of
hMLH1, ITGA9, and RBSP3 were high (45–55%) in mild dysplasia
and comparable in subsequent stages of tumor progression. Quantitative
RT-PCR analysis showed reduced expression of these genes
in tumors concordant to their molecular alterations. An in vitro
demethylation experiment by 5-aza-2¢-deoxycytidine confirmed
the promoter hypermethylation of RBSP3 in Hep2 and UPCI:SCC084
cell lines. Functionally less-active RBSP3A isoform was predominant
in tumor tissues contrary to the adjacent normal tissue of
tumors where more active RBSP3B isoform was prevalent. In
immunohistochemical analysis, intense nuclear staining of hMLH1
and pRB (phosphorylated RB, the substrate of RBSP3) proteins
were seen in the basal layer of normal epithelium. In tumors, concordance
was seen between (i) low ⁄ intermediate level of hMLH1
expression and its molecular alterations; and (ii) intense nuclear
staining of pRB and RBSP3 alterations. Poor patient outcome was
seen with hMLH1 and RBSP3 alterations. Moreover, in absence of
human papilloma virus (HPV) infection, tobacco-addicted patients
with hMLH1, RBSP3 alterations, and nodal invasions showed poor
prognosis. Thus our data suggests that dysregulation of hMLH1,
ITGA9, and RBSP3 associated multiple cellular pathways are
needed for the development of early dysplastic lesions of the head
and neck.
 
Publisher Oxford University Press
 
Date 2010
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/74/1/CANCER_SCIENCE_101(6)1511%2D1520_;2010[80].pdf
Ghosh, Amlan and Ghosh, Susmita and Maiti, Guru Prasad and sabbir, Mohd.Golam and Zabarovsky, Eugene R and Roy, Anup and Roychoudhury, Susanta and Panda, Chinmay Kumar (2010) Frequent Alterations of the Candidate Genes hMLH1, ITGA9 and RBSP3 in early Dysplastic Lesions of Head and Neck: Clinical and Prognostic Significance. Cancer Science, 101 (6). pp. 1511-1520.
 
Relation http:/dx.doi.org/10.1111/j.1349-7006.2010.01551.x
http://www.eprints.iicb.res.in/74/