Anti-CDK4 (full length) polyclonal antibody

Centrosomes duplicate only once in coordination with the DNA replication cycle and have an important role in segregating genetic material. In contrast, most cancer cells have centrosome aberrations, including supernumerary centrosomes, and this correlates with aneuploidy and genetic instability. The tumor suppressors p16 (CDKN2A) and p15 (CDKN2B) (encoded by the familial melanoma CDKN2 locus) inhibit CDK4/6 activity and have important roles in cellular senescence. p16 is also associated with suppressing centrosomal aberrations in breast cancer; however, the role of p15 in centrosome amplification is unknown. Here, we investigated the relationship between p15 and p16 expression, centrosome number abnormalities, and melanoma progression in cell lines derived from various stages of melanoma progression. We found that normal human melanocyte lines did not exhibit centrosome number abnormalities, whereas those from later stages of melanoma did. Additionally, under conditions of S-phase block, p15 and p16 status determined whether centrosome overduplication would occur. Indeed, removal of p15 from p16-negative cell lines derived from various stages of melanoma progression changed cells that previously would not overduplicate their centrosomes into cells that did. Although this study used cell lines in vitro, it suggests that, during clinical melanoma progression, sequential loss of p15 and p16 provides conditions for centrosome duplication to become deregulated with consequences for genome instability.

Individuals with multiple primary melanomas have rates of germline CDKN2A pathogenic variants of 3%-18%, and are also frequent carriers of variants in the melanocortin-1 receptor. Few patients with numerous (>= 3) primary melanomas have been studied with respect to these or other potential germline pathogenic variants. We investigated 46 patients with >= 3 primary melanomas (3, n = 17; 4, n = 14; 5-14, n = 15) to determine if higher rates of germline pathogenic variants of CDKN2A, MC1R, or other cancer genes could explain their extreme melanoma phenotype. Most (43/46, 93%) patients had variants in MC1R and 11/46 (24%) had CDKN2A pathogenic variants, but only male sex and having two variants in MC1R correlated with increasing number of melanomas. Panel screening of 56 other cancer predisposition genes did not reveal other germline pathogenic variants associated with melanoma (CDK4, BAP1, POT1), although pathogenic variants in TP53, CHEK2, and BRCA2 were present in three separate patients and some patients had variants of uncertain significance. In summary, targeted germline sequencing of patients with >= 3 primary melanomas revealed a high rate of pathogenic variants in CDKN2A and other known cancer genes. Although further investigation of these pathogenic variants and variants of uncertain significance is needed, these results support cancer gene panel testing in individuals diagnosed with >= 3 melanomas.