Homozygous deletions of CDKN2A caused by alternative mechanisms in various human cancer cell lines

Abstract

The CDKN2A tumor-suppressor locus on chromosome band 9p21, which encodes p16(INK4A), a negative regulator of cyclin-dependent kinases, and p14(ARF1), an activator of TP53, is inactivated in many human cancers by point mutation, promoter hypermethylation, and, often, deletion. Homozygous deletions are unusually prevalent at this locus in very different human cancers. In the present study, we compared deletions in squamous cell carcinoma of the head and neck (SCCHN) cell lines to those in T-cell acute lymphatic leukemia (T-ALL), glioma, and bladder carcinoma (TCC) cell lines. Of 14 SCCHN lines, 10 showed homozygous deletions of CDKN2A, one displayed promoter hypermethylation with gene silencing, and one had a frameshift deletion in exon 2. Many deletion ends were in or proximal to the repetitive sequence clusters flanking the locus. Breakpoint junctions displayed variable microhomologies or insertions characteristic of DNA repair by nonhomologous end-joining. In general, deletions were much smaller in SCCHN than in TCC and glioma. In T-ALL, breakpoints were near consensus sites for recombination mediated by RAG (recombination activating genes) enzymes, and the structure of the junctions was consistent with this mechanism. We suggest that different mechanisms of CDKN2A deletion prevail in different human cancers. Aberrant RAG-mediated recombination may be responsible in T-ALL, and exuberant DNA repair by nonhomologous end-joining is the likely prevailing mechanism in SCCHN, but a distinct mechanism in TCC and glioma remains to be elucidated.

Microarray detection of multiple recurring submicroscopic chromosomal aberrations in pediatric T-cell acute lymphoblastic leukemia

“…Although sequencing of these breakpoints was not performed, the results would be consistent with a common mechanism for the formation of deletions in this disorder, as has been previously proposed. 6 Three of the smaller deletions involved CDKN2A, but were distal to and did not include CDKN2B. This result is consistent with previous reports that found CDKN2A deleted in 65% of T-ALL patients, whereas CDKN2B was deleted in only 23% of patients.…”

Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats

“…A similar deletion was found in some human squamous cell carcinomas of the head and neck. 33 It seems likely that a certain site where the genome is liable to be lost in the p16ink4a gene, and this may be associated with malignant transformation of some kinds of tumors. Generally, inactivation of p16ink4a is caused by homozygous deletions, methylations of the promoter or point mutations, and the frequencies and patterns of p16ink4a inactivation are different depending on the origins of tumors.…”

CDKN2A/BAlterations Impair Prognosis in AdultBCR-ABL1–Positive Acute Lymphoblastic Leukemia Patients

“…Taken together, these alterations result not only in proliferative advantages but also in increased susceptibility to the accumulation of additional genetic alterations that contribute to tumor progression and acquisition of more aggressive phenotypes. In almost all tumors (1)(2)(3)(4)(5), these cell-cycle defects are mediated by the inactivation of a region located in humans at chromosome arm 9p21.…”