title: SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit.
abstract: To understand the association of candidate tumour suppressor genes SH3GL2, p16(INK4a), p14(ARF), and p15(INK4b) in the pathogenesis of head and neck squamous cell carcinoma (HNSCC), we studied the deletion, mutation, and methylation of these genes in 61 dysplastic lesions and 94 HNSCC samples. In mild dysplasia, SH3GL2, p16(INK4a), and p14(ARF) showed a higher frequency of overall alterations (60-70%) than in p15(INK4b) (40%). However, in subsequent stages of tumour progression, the alteration frequency of these genes did not change significantly. One novel mutation in common exon 2 of p16(INK4a)/p14(ARF) and three in exon 9 of SH3GL2 were seen. Concordance was seen in the expression of these genes with their molecular alterations. Deletions of INK4A-ARF and p15(INK4b) have a significant poor patient outcome. The alterations of p16(INK4a), p14(ARF), and p15(INK4b) were positively correlated with tobacco and inversely with HPV, while SH3GL2 alterations were independent of these factors. Based on aetiological factors, four tumour subtypes were recognized: HPV(-)tobacco(-) (I), HPV(+)tobacco(-) (II), HPV(-)tobacco(+) (III), and HPV(+)tobacco(+) (IV). Groups III and IV showed a high frequency of p16(INK4a)/p14(ARF)/p15(INK4b) alterations with significant poor patient outcome in comparison to group II. Our findings suggest that deregulation of SH3GL2-associated signalling and p16(INK4a)/p14(ARF)/p15(INK4b)-mediated G1-S/G2-M checkpoints of cell cycle are independent pathways for the development of early dysplastic lesions of the head and neck.
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata 700026, India.
authors.forename: Amlan
authors.initials: A
authors.lastname: Ghosh
authors.forename: Susmita
authors.initials: S
authors.lastname: Ghosh
authors.forename: Guru P
authors.initials: GP
authors.lastname: Maiti
authors.forename: Mohammed G
authors.initials: MG
authors.lastname: Sabbir
authors.forename: Neyaz
authors.initials: N
authors.lastname: Alam
authors.forename: Nilabja
authors.initials: N
authors.lastname: Sikdar
authors.forename: Bidyut
authors.initials: B
authors.lastname: Roy
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Panda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D030361:Papillomavirus Infections / Q000150:complications; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000032:analysis; D012907:Smoking / Q000009:adverse effects; D015996:Survival Rate
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050762:Cyclin-Dependent Kinase Inhibitor p15; D012333:RNA, Messenger; C107640:SH3GL2 protein, human