Differential alterations of the genes in the CDKN2A-CCND1-CDK4-RB1 pathway are associated with the development of head and neck squamous cell carcinoma in Indian patients.
ABSTRACT The aim of this study was to analyse the alterations of the genes in the CDKN2A/CCND1/CDK4/RB1 pathway in the G1-S phase of the cell cycle during development of head and neck squamous cell carcinoma (HNSCC).
The alterations of these genes were analysed in 22 dysplastic lesions, 26 stage-I/II and 33 stage-III/IV HNSCC tumours of Indian patients.
The alterations [mutation, hypermethylation, homozygous deletion and loss of heterozygosity/microsatellite size alteration (LOH/MA)] in the CDKN2A were found to be highest in 57% of the samples, followed by CCND1 amplification and LOH/MA at the RB1 locus in 14% and 8.5% of the samples, respectively. No dominant CDK4 Arg24Cys mutation was seen in our samples. Comparatively high frequency of CDKN2A alterations (except homozygous deletion) was found in dysplastic head and neck lesions and remained almost constant or increased during progression of the tumour, whereas the homozygous deletion of CDKN2A and the alterations in CCND1 and RB1 genes were seen mainly in the later stages of the tumour.
Our study suggested that mutation/hypermethylation/allelic alterations (LOH/MA) of CDKN2A were associated with the development of dysplastic head and neck lesions. All the other alterations might provide some cumulative effect during progression of later stages of the tumour to have selective growth advantages.
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ABSTRACT: Cyclin-dependent kinase 4 (CDK4) together with its regulatory subunit cyclin D1, governs cell cycle progression through G1 phase. Cyclin-dependent kinase inhibitors, including p16INK4A in turn regulate CDK4. In particular, deregulation of the p16/CDK4/cyclin D1 complex has been established in a variety of human tumors including gliomas, sarcomas, melanoma, breast and colorectal cancer. However, changes in CDK4 have rarely been observed. In this study we used a combination of PCR-SSCP and direct sequencing for mutational screening of CDK4. DNA was isolated from peripheral blood leukocyte of patients with squamous cell carcinoma of head and neck, for screening germline mutations in coding regions of CDK4. Variations observed in exon 2 and 5 were three missense mutations, g5051G > C (Ser52Thr), g5095G > C (Glu67Gln), g5906C > A, g5907C > G (Pro194Ser) and novel frame shift mutations g7321_23delTGA, g7121_7122insG, g7143delG in exon 7 and 3'UTR respectively. In conclusion, two novel mutations were found in N terminal domain which indicates that CDK4 mutation may play a major role in the development and progression of squamous cell carcinoma of head and neck.Hereditary Cancer in Clinical Practice 08/2012; 10(1):11. DOI:10.1186/1897-4287-10-11 · 1.71 Impact Factor
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ABSTRACT: Zusammenfassung Die Inaktivierung von p16 und p14ARF wird als bedeutender Schritt der Tumorgenese des Oropharynxkarzinoms angesehen. Allelverluste in der Region dieser Gene werden in Mundschleimhautkarzinomen und deren Vorläuferläsionen angetroffen. Die vorliegende Studie sollte prüfen, in welchem Umfang Allelverluste bereits in Mundschleimhautleukoplakien auftreten und ob es anhand dieser Veränderungen möglich ist, Leukoplakien mit und ohne maligne Entartung zu unterscheiden. Darüber hinaus sollten geklärt werden, ob betroffene Leukoplakien Sequenzveränderungen der Gene p16 und p14ARF tragen, die eine Beeinträchtigung der Genfunktion bewirken können. Die Ergebnisse zeigten, dass „LOH“ (loss of heterozygosity) in Region der Gene p16 und p14ARF sowohl in Leukoplakien mit maligner Entartung als auch in klinisch entartungsfreien Leukoplakien auftreten, wobei sich die Allelverlusthäufigkeiten nicht signifikant unterscheiden. Insgesamt wurden in Leukoplakien seltener Allelverluste angetroffen als in den resultierenden Mundschleimhautkarzinomen (pMund- Kiefer- und Gesichtschirurgie 11/2007; 11(6):317-326. DOI:10.1007/s10006-007-0086-0
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ABSTRACT: To understand the importance of frequent deletion of chromosomal 11q23.3-24.3 region in cervical carcinogenesis, alterations (deletion/methylation/mutation/expression) of the candidate genes LOH11CR2A, EI24 and CHEK1 located in the region were analyzed in 29 cervical intraepithelial neoplasia (CIN), 112 cervical carcinoma (CACX) samples and two CACX cell lines. The deletion frequency of these genes was low in CIN than in CACX [CIN: CHEK1: 28%, EI24: 21%, LOH11CR2A: 15% and CACX: CHEK1: 51%, EI24: 41%, LOH11CR2A: 36%]. Similar trend was seen in promoter methylation of these genes [CIN: CHEK1: 10%, EI24: 3%, LOH11CR2A: 3% and CACX: CHEK1: 55%, EI24: 31%, LOH11CR2A: 14%]. Mutations of the genes are a rare event. Overall alterations (deletion and methylation) of CHEK1 and EI24 were associated with progression of CACX. Quantitative mRNA expression analysis showed reduced expression of the three genes in concordance to their molecular alterations. A shorter isoform of CHEK1 lacking exon 8, hence impaired in substrate binding capacity, was found in two samples. Immunohistochemical analysis showed nuclear expression of Chek1, p-Chek1 and Ei24 in tumor tissues, whereas the cell lines exhibited both nuclear and cytoplasmic expression of Chek1 and Ei24, as is also evident from Western blot analysis suggesting differential localization of the proteins. Alterations of CHEK1 and EI24 coupled with tumor stage and early sexual debut (≤ 19 years) predicted worst prognosis. Thus, our data suggest that inactivation of EI24 and CHEK1 through two independent mechanisms contributes to the development of CACX.International Journal of Cancer 10/2011; 129(8):1859-71. DOI:10.1002/ijc.25849 · 5.01 Impact Factor