We analysed the DNAs from 37 gliomas of several grades of malignancy for allelic loss of chromosome 9p and aberrations of the MTS1/p16 and MTS2/p15 genes.
To investigate whether CDKN2B and CDKN2 are involved in esophageal tumorigenesis, we studied homozygous deletion, intragenic mutation, and messenger RNA (mRNA) expression of CDKN2 and CDKN2B in nine esophageal squamous cancer cell lines.
One half of all cancer cell lines and one fourth of lung cancer cell lines examined to date contain homozygous deletions (i.e., both alleles lost) of CDKN2.
Molecular genetic studies have revealed that deletion of the p16 and p15 genes occurs frequently in cancer cell lines and in certain malignant neoplasms.
These results are consistent with the idea that p16 allelic variants that decrease Cdk interaction predispose individuals who carry them to an increased risk of cancer.
The tumor suppressor genes p16INK4A and p15INK4B map to the 9p21 chromosomal locus and are either homozygously deleted or mutated in a wide range of human cancer cell lines and tumors.
Loss of the p16 gene is frequent in and highly specific to lymphoid malignancies (54 of 183 [30%] in lymphoid tumor v2 of 219 [1%] in myeloid tumors; P < .0001).
Loss of heterozygosity studies in melanoma and pancreatic carcinoma from gene carriers strongly support the view that CDKN2 is a general tumour suppressor gene predisposing not only to melanoma but also to other malignancies.
Furthermore, CDKN2 mRNA levels were similar in the 9 cancer cell lines that retain CDKN2, as compared to normal human ovarian surface epithelial cell lines.
Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy.
Our data confirm the predicted reciprocity between Rb inactivation and p16 expression in a common human malignancy and define differential p16 expression as a fundamental distinction between NSCLC and SCLC.
In order to determine whether MTS-1 sequences are deleted or mutated in cell lines derived from these cancers, we performed PCR amplification of MTS-1 exons 1 and 2.
PCR-single strand conformational polymorphism analysis of CDKN2 exons 2 and 3 and MTS2 exon 2 failed to demonstrate mutations in either CDKN2 or MTS2 in any of the T- or B-cell malignancies, with two possible exceptions.
These results: (i) demonstrate that the phosphorylase deficiency is distributed among almost all the most important human cancers; (ii) confirm and extend the tumor types were p16INK4 gene inactivation is observable and (iii) suggest that deletions at 9p21 (in humans) or at syntenic chromosomes (in other species) might represent a general mechanism of p16INK4 gene loss of function and possibly, in turn, of cancer development and/or progression.
The inverse correlation of RB and p16INK4 expression and the absence of p16INK4 inactivation in RB (-/-) SCLC lines (0/48) confirms a common p16INK4/RB growth suppressor pathway in human cancers and provides evidence that p16INK4, and not an adjacent gene on chromosome 9p, is a specific target for mutational events.