Furthermore, p16 positivity varied between the control sarcomas based on tumor type as follows: 11/11 leiomyosarcomas, 8/11 pleomorphic undifferentiated sarcomas, 9/39 sarcomatoid carcinomas, 7/7 desmoid tumors, 1/3 endometrial stromal sarcomas, and 1/2 malignant gastrointestinal stromal tumors.
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.
MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation.
Molecular studies and p16 status confirmed the typical characteristics of gastrointestinal stromal tumors with an aggressive phenotype underscoring the need for a special interdisciplinary treatment and for achieving complete local excision with free margins.
Low expression of the nuclear p16INK4A form and strong expression of the cytoplasmic p16INK4A form both represent two independent parameters each associated with tumour progression in GISTs.
MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11%) and seven high-risk (70%) GISTs with two cases homozygously codeleted at both loci.
In patients with high-risk GIST, the expression of p16 expression was highly predictive for poor prognosis, i.e., the development of recurrence or metastases (P = .006) and poor survival (P = .004).
The coincidence of loss of p16 and overexpression of human telomerase reverse transcriptase seems to be in contradiction to the small size, the benign nature, and the limited growth potential of appendiceal gastrointestinal stromal tumors.
We have previously investigated the role of loss of p16(INK4A) by loss of heterozygosity and immunohistochemistry in the progression of GISTs and found that loss of heterozygosity of 9p and loss of p16 expression are confined to malignant GISTs.
To determine the practicability of immunohistochemical staining for p16 in clinical cases, we examined p16 protein expression in a group of 284 GISTs, a subset of which had long-term follow-up (median, 45 months; range, 1-204 months).
GISTs with low mRNA expression of the CDKN2A transcripts p16(INK4A) and p14(ARF) but high mRNA expression of CDK4, RB1, MDM2, TP53, and E2F1 were associated with aggressive clinical behavior and unfavorable prognosis, whereas GISTs with a low mRNA expression of CDK4, RB1, MDM2, TP53, and E2F1 were not.
The results indicated the loss of p16INK4a mRNA expression in 41% of the GISTs, mainly due to the homozygous deletion of both the p16INK4a gene and the p14ARF gene (24%).