Germ line mutations at CDKN2A locus are generally inherited founder mutations having a common ancestral origin, while de novo mutations appear to be exceedingly rare events , thus marking a peculiarity in the genetic of patient A. Although the precise endpoints of the deletion were not determined here, by aCGH it was shown to span from 19,934,142 to 22,069,983 Mb, thus being larger than those previously mapped by Pasmant . In fact, in addition to the CDKN2A/CDKN2B/CDKN2BAS gene cluster, the deletion extends in the telomeric end to comprise a large region up to the MLLT3 gene.
Similarly to the other deletions detected in association with melanoma and NST, the deleted region includes part of the CDKN2BAS gene, which on the contrary is not always included in the deletions occurring in melanoma kindreds lacking NST, as schematized in Figure 2B. CDKN2BAS gene, or ANRIL (antisense non-coding RNA in the INK4 locus), consists of 19 exons spanning a region of 126.3 kb located within the CDKN2B-CDKN2A gene cluster, and is transcribed in the antisense orientation in a long non-coding RNA involved in epigenetic silencing of CDKN2B-CDKN2A locus by polycomb repressive complexes . Genome-wide association studies have identified SNPs in CDKN2BAS associated with susceptibility to NST as well as to melanoma [22, 23]; interestingly, CDKN2BAS has been identified as a risk locus also for other cancers and diseases . Among the other genes comprised in the deleted region, FOCAD has been shown deleted in glioma tumors . Furthermore, in patient B, CGH analysis showed copy number gains on 4p14 and 6q24.3 chromosomal regions involving TCF25 and KLF3 genes respectively, which encode for transcription factors, representing potential candidates for further studies. In fact, TCF25, has been involved in embryonic development expressed in brain , and KLF3, has been reported to show rearrangements in different cancer types .
Our study shows that 9p21.3 deletion is neither necessary nor sufficient for the NST-melanoma syndrome. Of note, both patients developed melanoma on their head after radiotherapy for astrocytoma, thus adding to other evidence suggesting association of melanoma with exposure to ionizing radiation [28–32]; in addition, the TS of patient A, who was not treated for NST, did not develop melanoma, although she carried an identical 9p21.3 deletion (see Additional file 6: Figure S3). It results that young cancer patients treated with radiotherapy should be considered at risk for developing melanoma and their pigmented lesions should be carefully monitored by expert clinicians. In fact, although melanoma is a rare disease in the healthy childhood population, it occurs more frequently as second malignant neoplasm after childhood cancer  and should be closely monitored by regularly screen in the follow-up of survivors, which have an approximate 2.5-fold increased risk of melanoma . Furthermore, children with genetic syndromes may have unique pathophysiologies that necessitate careful evaluation and follow-up of skin alterations, since often dermatologists find unusual and atypical correspondences between clinic and dermoscopic parameters and the histological ones . A multifaceted approach including a thorough clinical history, visual examination and dermoscopic evaluation of suspicious skin lesions is recommended to increase the sensitivity and specificity for diagnosing melanoma in these young patients.