Loss of heterozygosity on chromosome 6 in HPV-16 positive cervical carcinomas carrying the DRB1*1501-DQB1*0602 haplotype.
High-risk human papillomaviruses (HPVs), specifically HPV-16 and -18, have been associated with the development of carcinoma in situ (CIS) and of invasive cervical cancer (CC). However, only a small fraction of HPV-infected women will show signs of disease progression, suggesting that other factors in the carcinogenic pathway are needed. We previously demonstrated that human leukocyte antigen (HLA) DRB1*1501-DQB1*0602 (high risk) was associated with the development of CIS and CC tumors in HPV-16-positive patients. To characterize the molecular changes that could be relevant to tumor progression, we compared the extent of loss of heterozygosity (LOH) on chromosome 6 in HPV-16-positive CIS patients who were carriers of high-risk and neutral HLA haplotypes. CIS and CC cases demonstrated similar LOH patterns. A wide range of LOH frequencies was found at 6p (10-53%) and 6q (5-28%) in CIS cases, suggesting that LOH is an early event in the carcinogenic process. A comparative analysis of LOH frequencies in the high-risk versus the neutral HLA haplotypes showed a statistically significant difference in the extent of LOH at 6p24-p25 (58.6% versus 25.8%; P = 0.018) and at 6p21.3 (79.3% versus 35.5%; P = 0.001), a region that contains the HLA complex. LOH at this region could affect genes encoding HLA class I-II molecules, as well as factors responsible for the assembly, transport, and stable expression of HLA molecules. These losses may be a reflection of both an abnormal immune response and a general genome-wide instability resulting from virus persistence.
Arias-Pulido
Hugo
H
Department of Molecular Genetics and Microbiology, University of New Mexico, Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131, USA.
Joste
Nancy
N
Wheeler
Cosette M
CM
D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics*; D000090266:Chromobox Protein Homolog 5; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D009361:Neoplasm Invasiveness; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*
C000715594:CBX5 protein, human; D005819:Genetic Markers; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D008562:Membrane Glycoproteins; D000090266:Chromobox Protein Homolog 5