|
The INK4a gene is located at the chromosome locus 9p21, a region that undergoes frequent hemi- and homozygous deletion in human cancers. Several lines of evidence suggest that INK4a is a bona fide tumor suppressor gene at 9p21. Germline mutations of INK4a have been detected in kindreds with familial melanoma and pancreatic adenocarcinoma. Somatic mutations or allelic deletions of INK4a have also been described in the majority of sporadic melanomas, pancreatic adenocarcinomas, Barrett's esophagus-related adenocarcinomas, transitional cell carcinomas of the bladder, head and neck squamous cell carcinomas, and a variety of other malignancies. Recent investigations have revealed a third mechanism of gene inactivation, involving hypermethylation of the INK4a promoter region, which may be the predominant pathway in some tumors.
An antibody for assessment of p16INK4a protein expression using immunohistochemistry (IHC) has been developed, and is applicable to routinely fixed archival tissues. Like all IHC assays, this technique has the advantage of detecting p16INK4a status irrespective of the mechanism of gene inactivation. For example, despite the low frequency of INK4a mutations or allelic deletions in this tumor, nearly 20% of gastric carcinomas demonstrate reduction or loss of p16INK4a expression by IHC, underscoring the importance of epigenetic mechanisms in downregulating protein expression. At the same time, the use of IHC has facilitated the evaluation of prognostic factors, such as the association between the loss of p16INK4a expression in gastric cancers and the presence of lymph node metatstasis and poor overall survival. Similarly, loss of p16INK4a expression by IHC has been correlated with invasion and metastases in malignant melanomas, while head and neck premalignant lesions with p16INK4a loss were associated with a significantly increased risk of progression to carcinoma. The adverse prognostic effects of loss of p16INK4a expression have been extended to a variety of tumors, both carcinomas and sarcomas, reiterating the value of p16INK4a IHC as a feasible biomarker in risk stratification.
Veripath OncoDiagnostics offers p16INK4a as part of the standard esophagus, pancreas and bladder cancer panels, but it can also be ordered individually. Currently, we are using an automated image analysis system to quantitatively score percentage positivity and intensity grade for p16INK4a finally reflected in a histoscore on each evaluation. For more information contact Dr Raheela Ashfaq at Veripath OncoDiagnostics at 214.645.7053 or Raheela.Ashfaq@UTSouthwestern.edu.
Selected references:
1. Gallo O et al. Cumulative prognostic value of p16/CDKN2 and p53 oncoprotein expression in premalignant laryngeal lesions. J Natl Cancer Inst 89:1161; 1997
2. Huang CI et al. p16 expression is associated with a poor prognosis in squamous cell carcinoma of the lung. Br J Cancer 82:374; 2000
3. Merlo A et al. 5'CpG island methylation is associated with transcriptional silencing of the tumor suppressor p16/CDKN2/MTS1 in human cancers. Nature Med 1:686; 1995
4. Reed AL et al. High frequency of p16 (CDKN2/MTS-1/INK4a) inactivation in head and neck squamous cell carcinoma. Cancer Res 56:3630; 1996
5. Talve L et al. Loss of expression of p16INK4/CDKN2 gene in cutaneous malignant melanoma correlates with tumor cell proliferation and invasive stage. Int J Cancer 74:255; 1999
|
