Abstract
Missense and frame-shift mutations within the dimer forming domain of the caspase 8 gene have been identified in several cancers. However, the genetic status of this region in precancerous lesions, like oral submucous fibrosis (OSMF), and well differentiated oral squamous cell carcinomas (OSCCs) in patients from southern region of India is not known, and hence the present study was designed to address this issue. Genomic DNA isolated from biopsy tissues of thirty one oral submucous fibrosis and twenty five OSCC samples were subjected to PCR amplification with intronic primers flanking exon 7 of the caspase 8 gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the status of mutation. Sequence analysis identified a frame-shift and a novel missense mutation in two out of twenty five OSCC samples. The frame-shift mutation was due to a two base pair deletion (c.1225_1226delTG), while the missense mutation was due to substitution of wild type cysteine residue with phenylalanine at codon 426 (C426F). The missense mutation, however, was found to be heterozygous as the wild type C426C codon was also present. None of the OSMF samples carried mutations. The identification of mutations in OSCC lesions but not OSMF suggests that dimer forming domain mutations in caspase 8 may be limited to malignant lesions. The absence of mutations in OSMF also suggests that the samples analyzed in the present study may not have acquired transforming potential. To the best of our knowledge this is the first study to have explored and identified frame-shift and novel missense mutations in OSCC tissue samples.
Highlights
Caspase 8 is a cysteine dependent endoprotease that plays a key role in the regulation of apoptosis (Alenzi et al, 2010; Li et al, 2014), an event which is known to be essential in growth and development of embryo, and maintenance of tissue homeostasis (Andon et al, 2013; Weinlich et al, 2013)
To know whether caspase 8 was altered in precancerous oral submucous fibrosis (OSMF) lesions with mild dysplastic features and well differentiated oral squamous cell carcinomas (OSCCs) lesions, and to understand its association with carcinogenesis, we screened for mutations in the dimer forming domain coded by exon 7 of caspase 8 gene in thirty one OSMF and twenty five OSCC tissue samples obtained from patients
AIn the present study, we have reported the identification of a frame-shift mutation and a novel missense mutation, C426F in the dimer forming domain coded by exon 7 of caspase 8 gene in two OSCC tissue samples
Summary
Caspase 8 is a cysteine dependent endoprotease that plays a key role in the regulation of apoptosis ( referred as programmed cell death) (Alenzi et al, 2010; Li et al, 2014), an event which is known to be essential in growth and development of embryo, and maintenance of tissue homeostasis (Andon et al, 2013; Weinlich et al, 2013). Both activation of caspase -8 and -9 involves cleaving off of the N-terminal prodomain, which is made of two DED domains (Death Effector Domain) in caspase 8, and a single CARD domain (Caspase Recruitment Domain) in caspase 9, followed by dimerization of the larger (p20) and smaller (p10) subunits from each caspase -8 or -9 molecules to form heterotetramer (p20-p10) 2 Subsequent to their activation, both caspase -8 and -9 binds with effector caspases -3, -6 and -7 to cleave, activate and set the apoptosis program in motion To the best of our knowledge this is the first study to have explored and identified frame-shift and novel missense mutations in OSCC tissue samples
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