Comprehensive genomic analysis of squamous cell carcinoma of the head and neck
Researchers from the Cancer Genome Atlas report for the first time distinctive patterns of somatic alteration potentially amenable to molecularly targeted therapies
- Date: 08 Apr 2013
- Topic: Pathology/Molecular biology / Translational research / Head and neck cancers
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumour which displays distinctive patterns of somatic alteration potentially amenable to molecularly targeted therapies. The researchers document for the first time using the Cancer Genome Atlas data, the role of an oncogenic virus in the human cancer genome. The results were presented by Dr David Hayes, an associate professor at the University of North Carolina (UNC), who practices otolaryngology at the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, USA. He presented data on behalf of the Cancer Genome Atlas at the AACR Annual Meeting 2013 in Washington, D.C., April 6-10.
HNSCC is one of the leading causes of cancer death worldwide. Most cancers are tobacco-related, although an increasing number of tumours are found in non-smokers in association with the human papilloma virus (HPV).
The Cancer Genome Atlas is conducting DNA, RNA and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression, promoter methylation, and reverse-phase protein arrays on surgically resected samples from previously untreated patients with HNSCC. The researchers reported for the first time the results for 279 samples.
HNSCC found to be genomically heterogeneous
In this study eighty percent of the patients reported a history of smoking, a median age was 61 years (range: 19-90), and 27% of enrolled patients were female. The researchers identified more than 30 sites of significant somatic copy number alteration. HNSCC is a tobacco-related cancer, and one of the striking things the researchers observed was a high degree of similarity to other squamous tumours, including lung squamous cell carcinoma. Lessons learned from studying the similarities and differences between tumours, such as these copy number alterations, will be one of the angles researchers will follow to better understand the pathways altered in cancer.
However, some notable somatic copy number alteration were absent in HNSCC: PDGFRA amplification and deletion of FOXP. Similarly, somatic copy number alteration were compared between HPV-positive and HPV-negative tumours identifying numerous differences, including a paucity of receptor tyrosine kinase alterations in HPV-positive tumours and novel deletions in chromosome 11q and 14q. Exome sequencing revealed at least 15 significantly mutated genes including: CDKN2A, TP53, PIK3CA, FAT1, MLL2, TGFBR2, HLA-A, NOTCH1, HRAS, NFE2L2, and CASP8.
Consideration of differences between HPV-positive and HPV-negative tumours suggested differences which included nearly universal alteration of TP53 and frequent p16 mutations in HPV-negative tumours. Few TP53 or CDKN2A mutations were observed in HPV-positive samples.
Strikingly, a large number of co-occurring genomic alterations were observed. For example, mutations of HRAS were observed nearly universally in combination with either CASP8 or FAT1. All three of these mutations were absent in HPV-positive patients.
mRNA expression profiling revealed four distinct expression subtypes, each one enriched with distinct somatic copy number alteration and mutational profiles: classical, basal, mesenchymal, and atypical. Deep sequencing by multiple platforms allowed for a detailed accounting of the role of HPV in alterations of the cancer genomes of HNSCC patients, including integration sites, disruption of tumour suppressor genes, and more complex rearrangements.
HNSCC - a heterogeneous tumour which displays distinctive patterns of somatic alteration potentially amenable to molecularly targeted therapies
Commenting on identified differences in alterations between tumours infected with the HPV and those that were negative for the virus, Prof. Hayes said that “the current report greatly clarifies an observation that has been made in smaller cohorts of patients with HNSCC that EGFR gene amplification is infrequent in tumours that are infected with HPV but that these same tumours have a high rate of PIK3CA gene mutations”.
This finding raises questions about the efficacy of the EGFR inhibitor in the treatment of metastatic HNSCC in patients with HPV-positive tumours, according to the study researchers. “It also suggests that these patients may benefit from treatment with the inhibitors of PIK3CA that are in development”, according to Prof. Heyes. However, he warned that “any treatment conclusions should be based on treatment data”, which were not part of the Cancer Genome Atlas study.
The researchers hope that their study will become a landmark research tool for HNSCC for many years.
Thank you for rating!
You have already rated this page, you can only rate it once!