Loss of heterozygosity on chromosome 6 in HPV‐16 positive cervical carcinomas carrying the DRB1*1501‐DQB1*0602 haplotype

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Abstract
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.