The p16INK4a/CDKN2A tumor suppressor and its relatives

The INK4A/ARF locus and its two gene products.

The familial melanoma gene (INK4a/MTS1/CDKN2) encodes potent tumor suppressor activity. Although mice null for the ink4a homolog develop a cancer-prone condition, a pathogenetic link to melanoma susceptibility has yet to be established. Here we report that mice with melanocyte-specific expression of activated H-rasG12V on an ink4a-deficient background develop spontaneous cutaneous melanomas after a short latency and with high penetrance. Consistent loss of the wild-type ink4a allele was observed in tumors arising in ink4a heterozygous transgenic mice. No homozygous deletion of the neighboring ink4b gene was detected. Moreover, as in human melanomas, the p53 gene remained in a wild-type configuration with no observed mutation or allelic loss. These results show that loss of ink4a and activation of Ras can cooperate to accelerate the development of melanoma and provide the first in vivo experimental evidence for a causal relationship between ink4a deficiency and the pathogenesis of melanoma. In addition, this mouse model affords a system in which to identify and analyze pathways involved in tumor progression against the backdrop of genetic alterations encountered in human melanomas.

/pdf/cooperative-effects-of-ink4a-and-ras-in-melanoma-1s679fr4vh.pdf

Cooperative effects of INK4a and ras in melanoma susceptibility in vivo

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(98)01236-5.pdf

The INK4a/ARF tumor suppressor: one gene—two products—two pathways

Investigative interest in atypical nevi and familial melanoma has contributed to the identification of several candidate melanoma loci within the human genome. Molecular defects in both tumor suppressor genes and oncogenes have been pathogenically linked to melanoma in recent studies. Of the loci currently characterized, the major gene resides on chromosome 9p and encodes a tumor suppressor designated p16. This gene, which is also known as CDKN2A, is either mutated or deleted in a large majority of melanoma cell lines, as well as in many uncultured melanoma cells and in the germline of melanoma kindreds. A novel aspect of the p16 locus is that it encodes not just one but two separate gene products that are transcribed in alternative reading frames. Both products function as negative regulators of cell cycle progression. The p16 protein itself executes its effects by competitively inhibiting cyclin-dependent kinase 4, which is a factor necessary for cellular progression through a major regulatory transition of the cell division cycle. Inherited and acquired deletions or point mutations in the p16 gene increase the likelihood that potentially mutagenic DNA damage will escape repair before cell division. Notably, the second product of the locus, ARF (for alternative reading frame), regulates cell growth through independent effects on the p53 pathway. Although there is little evidence that ARF by itself is involved in the pathogenesis of melanoma, deletions at the p16 locus disable two separate pathways that control cell growth. These recent advances open up the possibility of genetic testing for melanoma susceptibility in the setting of familial melanoma and suggest novel therapeutic strategies for melanoma based on gene therapy or small molecule mimicry targeted to the correction of defects in the p16 regulatory pathway. (J Am Acad Dermatol 2000;42:705-22.) Learning Objective: At the conclusion of this learning activity, participants should be familiar with the historical aspects of melanoma genetics and should have a greater understanding of the CDKN2A(p16)/ARF tumor suppressor genes.

Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors.

Homozygous deletions of 9p21, including the cyclin-dependent kinase inhibitor genes p16INK4 and p15INK4B, have been reported frequently in melanoma (as well as other tumor) cell lines. Germline mutations within the p16INK4 gene have also been described in a proportion of familial melanoma kindreds, suggesting that p16INK4 is the 9p21 "melanoma" gene. We have previously concluded that deletion of this chromosomal region can occur early (before metastasis) and in vivo in sporadic melanoma due to the identification of identical hemizygous losses on 9p21 in six autologous melanoma cell lines established from an individual patient (DX). These related cell lines have now been used to evaluate the timing of deletion/mutation of the p16INK4 and p15INK4B genes during tumor progression in melanoma. Surprisingly, homozygous deletions of a < or = 200-kb region surrounding p15INK4B, but not p16INK4, were detected in all six cell lines. Furthermore, single strand conformation polymorphism and sequencing analysis of the remaining p16INK4 allele in each case revealed only one intragenic mutation (in DX-6), whereas Western analysis provided evidence that p16INK4 protein was expressed in all six instances. These findings, taken together with those generated on other unrelated melanoma tumors and cell lines, suggest that hemizygous loss (or haplo-insufficiency) of the p16INK4 gene may be enough to place a melanocyte on a tumor pathway, and/or that the p16INK4 gene is not the sole 9p21 locus targeted in sporadic melanoma.

https://cancerres.aacrjournals.org/content/canres/55/23/5531.full.pdf

Homozygous loss of the p15INK4B gene (and not the p16INK4 gene) during tumor progression in a sporadic melanoma patient.

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Homozygous loss of the p15INK4B gene (and not the p16INK4 gene) during tumor progression in a sporadic melanoma patient.