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Detection of novel HPV mutations and chromosomal number imbalance (CNI) in laryngeal cancer using next-generation sequencing (NGS).
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Background: We selected HPV-associated laryngeal papillomas and squamous cell carcinomas for genomic analysis of viral induced benign and malignant neoplasms. The nearly universal presence of HPV in Recurrent Respiratory Papillomatosis (RRP) and in certain squamous cell carcinomas provides an important model for the study of biomarkers and clinical outcomes as well as the generation of robust panels of viral and genomic mutation biomarkers that can be used to follow disease progression. Methods: DNA was isolated from biopsies of three patients and sequenced on a NGS Illumina HiSeq platform. The sequences were compartmentalized in 250kbp bins, normalized, and compared to the mean (+/- 3SD) of Chronix controls to identify regions of chromosomal number imbalance (CNI). Sequences were also compared to databases with known viral genomes. Results: Sample 1: an exophytic, focally invasive, HPV positive (PCR), squamous cell carcinoma from a never-smoker. The full genome of HVP16 was detected in low amount (~ 500 sequences/10 million sequences, average coverage=42 fold). Mismatches to the closest reference HPV16 strain isolate were found in protein (number of mismatches) E7 (1), E1 (2), E2 (4), E4 (1), L2 (3) and L1 (4). Sample 2: from a RRP patient, contained the full genome of HPV6, also in low amount (~300 sequences/10 million sequences, average coverage = 24 fold). Interestingly, the HPV long control region was a variant as yet undescribed. Sample 3: from a RRP patient whose papillomas slowly and spontaneously regressed, did not contain any detectable viral DNA. Only the HPV16 squamous cell carcinoma contained CNI with gains at chromosomes 3q and 8p, and losses at chromosomes 3p, 11q, 12p, and 21q consistent with a malignant transformation. Conclusions: NGS reveals the identity and copy number of viral genes directly from clinical samples. This approach has revealed new HPV mutations not described by current viral analytical procedures
Abstracts by Howard B. Urnovitz:
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Category: Tumor Biology - Circulating Tumor Cells
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