Germline duplication of chromosomes 10p15.3 and Yp11.32 in a man with learning disability and early onset cutaneous malignant melanoma

Newer molecular cytogenetic analysis methods such as fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) have facilitated identification of cytogenetic abnormalities in solid tumors. In parallel, CGH has been rapidly adopted in the clinical evaluation of individuals with developmental delays. We recently evaluated an 18-year-old male with a history of learning disabilities who developed a cutaneous malignant melanoma (CMM) in a non-sun-exposed area. He was the only child born to a non-consanguineous couple. His father was a healthy 40-year-old of mixed European ancestry. His mother was of Italian ancestry and had died at age 30 of an insulin reaction from type 1 diabetes. There was no family history of melanoma or any cancers at unusual ages. He developed a rapidly enlarging lesion in his posterior scalp that was initially thought to be inflammatory but subsequently became black. A diagnostic biopsy showed a Clark level IV nodular melanoma, 3.3 mm in thickness with ulceration and with one occipital node positive for a micrometastatic melanoma. On his physical examination he was a well nourished young man of normal stature with dark brown hair, brown eyes and relatively fair skin with no evidence of excessive solar damage or tanning (Fig. 1). There were no unusual pigmented lesions anywhere else on examination. He had been healthy prior to this diagnosis, but was noted to have had significant learning disabilities. Clinical mutation analysis showed no mutations within the CDKN2A gene and sequence analysis of CDK4 gene showed no mutations [GeneDX, Gaithersburg, MD] but microarray analysis showed two areas of duplication including chromosomes 10p15.3 and X/Yp11.32 (pseudoautosomal region). Microarray analysis of thepatient’s father showed that hewas a carrier of the X/Yp11.32 duplication and therefore confirmed its origin as the Y chromosome. We cannot determine if the chromosome 10p15.3 duplication was of maternal origin or was de novo. The final report from Signature Genomic Laboratory was reported as arr cgh Xp22.33 Yp11.32 (RP13-76L22, RP11-946P8, RP11-309M23)x3 pat, 10p15.3 (RP11-105A22, RP1158N22, RP11-89K18)x3. Several CMM susceptibility loci have been reported, including the tumor suppressor gene, CDKN2A on chromosome 9p21; the CDK4 oncogene on chromosome12q14; and linkage to both 1p36 and 1p22 in melanoma family studies [Kamb et al., 1994; Zuo et al., 1996; Gillanders et al., 2003; Molven et al., 2005]. In addition, Petty et al. [1993a,b] reported an unbalanced reciprocal translocation of chromosome 5 and 9, an important factor of melanoma tumorigenesis. Other genes reported to be low-risk susceptibility variants include MC1R on chromosome 16q24.3, ARLTS1 on chromosome 1q42, NBS1 on chromosome 8q21, and others [Box et al., 2001; Frank et al., 2006; Meyer et al., 2007]. None of these seem directly relevant to the current case report. A recent study of 76 melanoma cell lines using a genome-wide high-density single nucleotide microarray showed frequent chromosomal losses of 9p, 10p, 10q, 9q, 6q, 11q, 17 p, and 5q, which are consistent with prior reports [Poetsch et al., 2003;