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.

Genome-wide analysis of allelic imbalance in prostate cancer using the Affymetrix 50K SNP mapping array

“…Combined global analysis of LOH and genomic copy number data showed that LOH in PCa correlates positively to copy loss. Our data showed no signs of uniparental disomy in LOH regions, as otherwise recently reported to be a common mechanism in advanced breast cancer (Murthy et al, 2002;Cleton-Jansen et al, 2004), acute myeloid leukaemia , medullablastoma (Langdon et al, 2006) and basal cell carcinomas (Teh et al, 2005). Loss of heterozygosity and concomitant copy loss at chromosomes 8p, 10q, 13q,16q and 21q were found with an equal frequency in both localised and metastatic tumours, and were not associated with tumour stage or grade.…”

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

“…The acquisition of aUPD is nonrandom, varies within and between cancers, 15,29,30 and in leukemia is frequently associated with homozygous gene mutation. [20][21][22][23][24] In FL the mutational status of genes is less established and the secondary events more complex.…”

Using high-throughput SNP technologies to study cancer

“…This approach has opened a whole new area of cancer research. Such studies have included the evaluation of basal cell carcinomas (Teh et al, 2005), Wilms' tumors (Yuan et al, 2005), ovarian tumors (Thompson et al, 2005), osteosarcomas , prostate cancer (Lieberfarb et al, 2003), small cell and nonsmall cell lung carcinomas Zhao et al, 2004;Ishikawa et al, 2005), breast cancer Herr et al, 2005), squamous cell carcinomas , bladder tumors (Koed et al, 2005), melanomas (Garraway et al, 2005), acute lymphoblastic leukemias (Irving et al, 2005), and acute myeloid leukemias . In nearly all of these cases, novel locations of allelic imbalance have been identified.…”