The Landscape of Somatic Copy Number Alterations in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Somatic copy number alterations (CNAs) play a significant role in the development of this lethal cancer. In this study, we present a meta-analysis of CNAs for a total of 1,395 HNSCC samples. Publicly available R packages and in-house scripts were used for genomic array data processing, including normalization, segmentation and CNA calling. We detected 125 regions of significant gains or losses using GISTIC algorithm and found several potential driver genes in these regions. The incidence of chromothripsis in HNSCC was estimated to be 6%, and the chromosome pulverization hotspot regions were detected. We determined 323 genomic locations significantly enriched for breakpoints, which indicate HNSCC-specific genomic instability regions. Unsupervised clustering of genome-wide CNA data revealed a sub-cluster predominantly composed of nasopharynx tumors and presented a large proportion of HPV-positive samples. These results will facilitate the discovery of therapeutic candidates and extend our molecular understanding of HNSCC.

Keywords: chromothripsis; copy number alteration; genomic array; head and neck squamous cell carcinoma; meta-analysis.

Figure 1

Genome-wide frequency plot of copy number alterations. Copy number gains and losses are represented in red and blue, respectively.

Figure 2

Significantly altered regions and genes identified by GISTIC algorithm. The significance of recurrent amplification and deletion is plotted across the genome. Some of the identified potential cancer driver genes are shown at the corresponding peaks.

Figure 3

The genomic landscape of chromothripsis and copy number alteration breakpoints. The outermost circle represents potential cancer driver genes located in chromosome pulverization regions or the breakpoint hotspots. The next circle represents hotspots of chromothripsis region. The third circle shows the breakpoint-prone genomic regions. The innermost circle represents common fragile sites and non-fragile regions in red and green, respectively.

Figure 4

Unsupervised clustering of DNA copy number alteration data. The 1,395 HNSCC samples are arranged along the x-axis and ordered according to their copy number profiles. Chromosome numbers are indicated along the y-axis. Key clinical parameters associated with the samples are displayed in the column header. Red indicates copy number gain, and blue indicates copy number loss. The red line at the bottom of the figure represents a sub-cluster containing a large proportion of HPV-positive samples. The blue line at the bottom of the figure shows a sub-cluster consisted of samples harboring few copy number alterations. NA, not available.