Genomic profiling identifies common HPV-associated chromosomal alterations in squamous cell carcinomas of cervix and head and neck

Abstract

Background: It is well known that a persistent infection with high-risk human papillomavirus (hrHPV) is causally involved in the development of squamous cell carcinomas of the uterine cervix (CxSCCs) and a subset of SCCs of the head and neck (HNSCCs). The latter differ from hrHPV-negative HNSCCs at the clinical and molecular level.

Methods: To determine whether hrHPV-associated SCCs arising from different organs have specific chromosomal alterations in common, we compared genome-wide chromosomal profiles of 10 CxSCCs (all hrHPV-positive) with 12 hrHPV-positive HNSCCs and 30 hrHPV-negative HNSCCs. Potential organ-specific alterations and alterations shared by SCCs in general were investigated as well.

Results: Unsupervised hierarchical clustering resulted in one mainly hrHPV-positive and one mainly hrHPV-negative cluster. Interestingly, loss at 13q and gain at 20q were frequent in HPV-positive carcinomas of both origins, but uncommon in hrHPV-negative HNSCCs, indicating that these alterations are associated with hrHPV-mediated carcinogenesis. Within the group of hrHPV-positive carcinomas, HNSCCs more frequently showed gains of multiple regions at 8q whereas CxSCCs more often showed loss at 17p. Finally, gains at 3q24-29 and losses at 11q22.3-25 were frequent (>50%) in all sample groups.

Conclusion: In this study hrHPV-specific, organ-specific, and pan-SCC chromosomal alterations were identified. The existence of hrHPV-specific alterations in SCCs of different anatomical origin, suggests that these alterations are crucial for hrHPV-mediated carcinogenesis.

Figure 1

Result from the unsupervised hierarchical clustering analysis. Cluster 1 contains in majority hrHPV-positive carcinomas, as is indicated by the black boxes in the legend underneath the heatmap (p < 0.0001).

Figure 2

Frequency plots for all 3 sample groups. The frequency of gains (positive axis) and losses (negative axis) are shown for A. hrHPV-negative HNSCCs, B. hrHPV-positive HNSCCs and C. CxSCCs for chromosome 1–22.

Figure 3

Summary of common and specific chromosomal alterations in the different sample groups. Chromosome arms showing frequent alterations (>50%) in one or more sample groups (hrHPV-positive HNSCCs; hrHPV-negative HNSCCs; CxSCCs) are shown in a Venn diagram. ↑ indicates gain; ↓ indicates loss

Figure 4

Genomic coordinates of A. losses at chromosome 13 and B. gains at chromosome 20 are shown for all hrHPV-positive carcinomas. Chromosomal alterations in CxSCCs are shown by dashed lines and alterations in hrHPV-positive HNSCCs by solid lines. In C. the smallest regions of overlap (SROs) between hrHPV-positive carcinomas at chromosome 13 and 20 are summarised.