Loss of Heterozygosity Associated with Uniparental Disomy in Breast Carcinoma

Abstract

Loss of heterozygosity is commonly assumed to be due to deletion of the appropriate genomic region in one chromosome within a neoplastic cell but may be due to other mechanisms such as mitotic nondisjunction or somatic recombination leading to uniparental heterodisomy. We chose to study the genomic regions surrounding the p53 and RB1 tumor suppressor genes in breast carcinoma to evaluate the different mechanisms that could mediate loss of heterozygosity. A microsatellite analysis of polymorphic markers in 50 breast cancer samples showed loss of heterozygosity for at least 1 of the 10 markers analyzed in 50% of the tumors studied, and an overall 8.47% of the informative loci showed loss of heterozygosity. All of the cases with loss of heterozygosity were further analyzed for gene copy number of the tumor suppressor genes RB1 and p53 by fluorescence in situ hybridization of either tumor touch preparations or microdissected tumor nuclei with specific genomic probes. Surprisingly, all samples showed the presence of both copies of tumor suppressor genes, including 4/50 cases showing loss of heterozygosity of tumor suppressor genespanning markers. One of the 4 cases showed loss of heterozygosity of markers spanning a distance of 6 cM over the RB1 gene, with normal copy numbers of the gene. Three other cases showed loss of heterozygosity of markers within the tumor suppressor gene (RBI or p53) and at least one other spanning marker. No cases showed a simultaneous reduction to homozygosity of markers both near the tumor suppressor gene and distal loci. We suggest that the presence of both copies of the tumor suppressor gene in the cases with loss of heterozygosity of spanning markers and internal markers for that tumor suppressor gene could be explained by somatic recombination resulting in uniparental disomy, but not mitotic nondisjunction or deletion. As the mechanism for physical deletion of a chromosome may be different from those mediating somatic recombination, study of this phenomenon may identify different pathways of genomic instability that may be of diagnostic or treatment significance in breast or other cancers, particularly in those treatments based upon DNA-altering agents.

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.…”

Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays

“…Uniparental disomy or UPT are exceptional derivations of a pair of offspring chromosomes from one parent only (Engel, 1980) and cause an increased risk of recessive disorders, such as Wiedemann-Beckwith (Henry et al, 1991), Prader-Willi (Nicholls et al, 1989) and Angelman syndromes (Malcolm et al, 1991) owing to reduction to homozygosity (Engel, 1993). Furthermore, UPD regions have been shown to contain genes responsible for carcinogenesis, which have been implicated in Wilms' tumor (Grundy et al, 1994), leukemia (Raghavan et al, 2005) and breast cancer (Murthy et al, 2002), but have never been described in HCC. Our data showed that UPD is frequently observed on chromosome 6q, 10q and 13q, where LOH is observed repeatedly and contains suppressor genes, such as PTEN, DMBT1, BRCA2, RB and DLC2.…”

“…Allelic changes, including hemizygous deletion with a gain of the opposite allele, so-called uniparental disomy (UPD) or trisomy (UPT), are important in elucidating the molecular mechanisms of cancer (Engel, 1980). For example, accurate determination of the copy number of each allele separately in the UPD region, which may contain a region of methylation or null mutation of tumor suppressor genes, may allow the mechanism of carcinogenesis to be determined more clearly and comprehensively (Grundy et al, 1994;Murthy et al, 2002;Raghavan et al, 2005). In addition, accurate measurement of changes in copy number using high-resolution methods will help in the detection of heterogeneous populations among cancer cells (Benetkiewicz et al, 2005;Buckley et al, 2005).…”

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.…”