Gain of CCND1May Occur Too Infrequently in Cutaneous Melanoma, and Too Late in Melanomagenesis, to Be Diagnostically Useful: Genomic Analysis of 88 Cases

Genomic analysis is an important tool in the diagnosis of histologically ambiguous melanocytic neoplasms. Melanomas, in contrast to nevi, are characterized by the presence of multiple copy number alterations. One such alteration is gain of the proto-oncogene CCND1at 11q13. In melanoma, gain of CCND1has been reported in approximately one-fifth of cases. Exact frequencies of CCND1gain vary by melanoma subtype, ranging from 15.8% for lentigo maligna to 25.1% for acral melanoma. We present a cohort of 72 cutaneous melanomas from 2017–2022 in which only 6 (8.3%) showed evidence of CCND1gain by chromosomal microarray. This CCND1upregulation frequency falls well below those previously published and is significantly lower than estimated in the literature (P< 0.05). In addition, all 6 melanomas with CCND1gain had copy number alterations at other loci (most commonly CDKN2Aloss, followed by RREB1gain), and 5 were either thick or metastatic lesions. This suggests that CCND1gene amplification may be a later event in melanomagenesis, long after a lesion would be borderline or equivocal by histology. Data from fluorescence in situ hybridization, performed on 16 additional cutaneous melanomas, further corroborate our findings. CCND1gain may not be a common alteration in melanoma and likely occurs too late in melanomagenesis to be diagnostically useful. We present the largest chromosomal microarray analysis of CCND1upregulation frequencies in cutaneous melanoma, conjecture 3 hypotheses to explain our novel observation, and discuss implications for the inclusion or exclusion of CCND1probes in future melanoma gene panels.