the bug Essay

Submitted By bdutting
Words: 667
Pages: 3

ffffffffffffffffffffffffffffffffffffffffffffffffffffffff.The major gene associated with melanoma is CDKN2A/p16, cyclin-dependent kinase inhibitor 2A, which is located on chromosome 9p21. This gene has multiple names (MTS1, INK4, and MLM) and is commonly called by the name of its protein, p16. It is an upstream regulator of the retinoblastoma gene pathway, acting through the cyclin D1/cyclin-dependent kinase 4 complex. This tumor suppressor gene has been intensively studied in multiple-case families and in population-based series of melanoma cases. CDKN2A controls the passage of cells through the cell cycle and provides a mechanism for holding damaged cells at the G1/S checkpoint to permit repair of DNA damage prior to cellular replication. Loss of function of tumor suppressor genes—a good example of which is CDKN2A—is a critical step in carcinogenesis for many tumor systems.

CDKN2A encodes two proteins, p16INK4a and p14ARF, both inhibitors of cellular senescence. The protein produced when the alternate reading frame (ARF) for exon 1 is transcribed instead of the standard reading frame exerts its biological effects through the p53 pathway. It mediates cell cycle arrest at the G1 and G2/M checkpoints, complementing p16’s block of G1/S progression—thereby facilitating cellular repair of DNA damage.

Mutations in CDKN2A account for 35% to 40% of familial melanomas.[62] A large case series from Britain found that CDKN2A mutations were present in 100% of families with seven to ten individuals affected with melanoma, 60% to 71% of families with four to six cases, and 14% of families with two cases.[63] A similar study of Greek individuals with melanoma found CDKN2A mutations in 3.3% of single melanoma cases, 22% of familial melanoma cases, and 57% of individuals with multiple primary melanomas.[73] Many mutations reported among families consist of founder mutations, which are unique to specific populations and the geographic areas from which they originate.[74-80]

Depending on the study design and target population, melanoma penetrance related to deleterious CDKN2A mutations differs widely. One study of 80 multiple-case families demonstrated that the penetrance varied by country, an observation that was attributed to major differences in sun exposure.[81] For example, in Australia, the penetrance was 30% by age 50 years and 91% by age 80 years; in the United States, the penetrance was 50% by age 50 years and 76% by age 80 years; in Europe, the penetrance was 13% by age 50 years and 58% by age 80 years. In contrast, a comparison of families with the CDKN2A mutation in the United Kingdom and Australia demonstrated the same cumulative risk of melanoma; for CDKN2A carriers, the risk of developing melanoma seemed independent of ambient UV radiation.[82] Another study of individuals with melanoma identified in eight population-based cancer registries and one hospital-based sample obtained a self-reported family history and sequenced