The majority (5/8) of MPNSTs in our analyses demonstrated homozygous or heterozygous deletions of CDKN2A, which may represent an early event following NF1 LOH in the malignant transformation of Schwann cells from plexiform neurofibroma to MPNST.
In mouse melanoma models with specific induced gene mutations including mutations of the Braf, Pten, and Cdkn2a genes, viral infection correlated with the extent of malignant transformation.
We also examined deletion of cyclin-dependent kinase inhibitor 4 (INK4) genes and mutation of p53 gene in combination with changes in the HTLV-I genome in acute type ATL to test whether host genetic changes promoted the malignant transformation of ATL cells that carry putative CTL escape mutations.
This study evaluated INK4a/ARF locus alterations in 26 patients (28 samples) deemed to be at increased risk for malignant transformation to squamous cell carcinoma due to the diagnosis of severe oral epithelial dysplasia.
Methylation of the DAPK and p16 genes, although not sufficient to dictate prognosis of the disease, should not be underestimated because it may form part of a process of genetic and epigenetic alterations that in the future could become relevant to malignant transformation.
Results of this study suggest that two different genetic alterations, the inactivation of the p16 gene and genetic instability, play roles in the malignant transformation of carcinoma in pleomorphic adenoma.
Our study suggests that: (1) polysomy 6 and p16 deletion may contribute to adenomatous change of IPMN; (2) polysomy 7, polysomy 18, p16 deletion, and p53 deletion play roles in malignant transformation of noninvasive IPMN; and (3) polysomy 7 and p53 deletion may be excellent diagnostic markers for invasive IPMN.
The observation that alterations of p14(ARF) and p16(INK4a), and also p53 mutations, occurred exclusively in the epithelial and transitional components of pleomorphic adenoma supports the theory that these areas are prone to malignant transformation to carcinoma in adenoma.
Some bladder primary tumors and some bladder and melanoma tumor cell lines contain mutations in both P16 and P53 at frequencies that suggest that p53 and p16 function in different pathways, each of which is important in suppressing malignant transformation.
Inactivation of the p16(INK4a)/Rb pathway may allow continuous cell division and critical telomere shortening, which induce genome instability, finally leading to malignant transformation.
It has been shown that the induction of p16(Ink4a) in premalignant lesions and its loss during malignant transformation is an important mechanism in the carcinogenesis of several tumours.
It has been suggested that the up-regulation of the tumour suppressor p16 gene and induction of senescence protect the phenotype of psoriatic involved skin from malignant transformation.
Tumor-suppressor gene p16 is an important negative cell-cycle regulator whose functional loss may significantly contribute to malignant transformation and progression.
Selective methylation was found in 19% for p16(INK4a), 36% for p15(INK4b), and 6.5% for both genes in MGUS, and frequencies were similar in MM suggesting that methylation of these genes is an early event, not associated with transition from MGUS to MM. p15(INK4b) and p16(INK4a) gene methylation might contribute to immortalization of plasma cells rather than malignant transformation in the natural history of MM.
Also suggested is that p16 has no role in the specific malignant transformation step from immortal premalignant lesions during the carcinogenesis of HPV-initiated cervical cancers.
The expression of the nuclear and cytoplasmic forms of p16 represent two independent mechanisms, and both seemed to control proliferation in response to oncogenic stimuli, protecting the cell from malignant transformation in BRAF-mutated GISTs.