Frequent loss of heterozygosity targeting the inactive X chromosome in melanoma.
After previous preliminary observations of paradoxical deletion events affecting the inactive X chromosome in melanoma, we have surveyed the X chromosome for deletions using 23 polymorphic microsatellite markers in 28 informative (female XX) metastatic melanomas. Ten tumors (36%) showed at least one loss of heterozygosity (LOH) event, and in two cases an entire chromosome showed LOH at all informative loci. Four distinct X chromosome smallest regions of overlap can be resolved. An 18.6-Mb region on the p arm involving 9 of 28 (32%) samples lies between the markers DXS1061 and DXS1068. An equally frequently deleted smallest region of overlap straddled the centromere, bounded by DX1204 on the p arm and DXS983 14.6 Mb away in Xq11-12. One tumor potentially defines this region more tightly to a 10.6-Mb smallest region of overlap bounded by DXS1190 and DXS981 that contains the androgen receptor (AR) gene. A 6.2-Mb deleted region can be defined between the markers DXS8051 and DXS9902 in 8 of 28 (28%) tumors. An additional, less frequently deleted region of 25.7 Mb was found on distal Xq between the markers DXS1212 and DXS1193 in 5 of 28 (18%) tumors. X inactivation analysis of five tumors with LOH, using the AR exon 1 CAG repeat, showed that in each case, the inactive, hypermethylated allele was the one deleted. Analysis of copy number in this region by quantitative PCR showed restoration to disomy and, in one case, trisomy at AR.
Indsto
James O
JO
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
Nassif
Najah T
NT
Kefford
Richard F
RF
Mann
Graham J
GJ
D000328:Adult; D000483:Alleles; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D008545:Melanoma / Q000235:genetics*; D018895:Microsatellite Repeats; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D011944:Receptors, Androgen / Q000235:genetics
D005819:Genetic Markers; D011944:Receptors, Androgen; D004247:DNA