title: Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event.
abstract: Basal cell carcinoma is the most common human cancer with increasing incidence reported worldwide. Despite the aberrant signaling role of the Hedgehog pathway, little is known about the genetic mechanisms underlying basal cell carcinomas. Towards a better understanding of global genetic events, we have employed the Affymetrix Mapping 10K single nucleotide polymorphism (SNP) microarray technique for "fingerprinting" genomewide allelic imbalance in 14 basal cell carcinoma-blood pair samples. This rapid high-resolution SNP genotyping technique has revealed a somatic recombination event-uniparental disomy, leading to a loss of heterozygosity (LOH), as a key alternative genetic mechanism to allelic imbalances in basal cell carcinomas. A highly conserved LOH region at 9q21-q31 was found in 13 of 14 (93%) basal cell carcinomas. Further statistical and fluorescence in situ hybridization analyses confirmed that the 9q LOH was a result of uniparental disomy in 5 of 13 (38%) basal cell carcinomas. De novo mutations in the Patched 1 gene (PTCH) were found in 9 of 13 (69%) basal cell carcinomas with 9q LOH. A second important locus, containing LOH at 6q23-q27 was found in 5 of 14 (36%) basal cell carcinomas, suggesting that the presence of an additional putative tumor suppressor gene may be contributing to basal cell carcinoma development. This study shows that the rate of 9q LOH in basal cell carcinomas has been previously underestimated. Furthermore, we provide the first evidence that uniparental disomy due to somatic recombination constitutes one of the mechanisms of LOH in basal cell carcinoma tumorigenesis.
authors.affiliation: Centre for Cutaneous Research, Institute of Cell and Molecular Science, England, United Kingdom. m.t.teh@qmul.ac.uk
authors.forename: Muy-Teck
authors.initials: MT
authors.lastname: Teh
authors.forename: Diana
authors.initials: D
authors.lastname: Blaydon
authors.forename: Tracy
authors.initials: T
authors.lastname: Chaplin
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Foot
authors.forename: Spyros
authors.initials: S
authors.lastname: Skoulakis
authors.forename: Manoj
authors.initials: M
authors.lastname: Raghavan
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Harwood
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Proby
authors.forename: Michael P
authors.initials: MP
authors.lastname: Philpott
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance; D001483:Base Sequence; D002280:Basal Cell Carcinoma / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface