3p Arm Loss and Survival in Head and Neck Cancer: An Analysis of TCGA Dataset

Cancers

Paul C. Boutros¹  Pencilla Lang²  Temitope Akintola³  John Yoo³  Laura Jarycki³  Adrian Mendez³  Peter Y. F. Zeng³  Hugh Andrew Jinwook Kim³  Halema Khan³  Anthony C. Nichols³  Kevin Fung³  David A. Palma³  John W. Barrett³  Mohammed Imran Khan³  Joe S. Mymryk³  Mushfiq Hassan Shaikh³  Xiaoxiao Deng³  Alana Sorgini³  Danielle MacNeil³  Mark Lee⁴  Luc G. T. Morris⁴  Krupal Patel⁵ 

[1] Department of Human Genetics, University of California, Los Angeles, CA 90095, USA;Department of Oncology, University of Western Ontario, London, ON N6A3K7, Canada;Department of Otolaryngology-Head and Neck Surgery, University of Western Ontario, London, ON N6A3K7, Canada;Memorial Sloan Kettering Cancer Center, Department of Surgery, New York, NY 10065, USA;Moffitt Cancer Center, Department of Otolaryngology, Tampa, FL 33612, USA;

关键词: head and neck cancer;    chromosome loss;    copy number alterations;    genomics;    mutational status;   

DOI  :  10.3390/cancers13215313

来源: DOAJ

【 摘 要 】

Loss of the 3p chromosome arm has previously been reported to be a biomarker of poorer outcome in both human papillomavirus (HPV)-positive and HPV-negative head and neck cancer. However, the precise operational measurement of 3p arm loss is unclear and the mutational profile associated with the event has not been thoroughly characterized. We downloaded the clinical, single nucleotide variation (SNV), copy number aberration (CNA), RNA sequencing, and reverse phase protein assay (RPPA) data from The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas HNSCC cohorts. Survival data and hypoxia scores were downloaded from published studies. In addition, we report the inclusion of an independent Memorial Sloan Kettering cohort. We assessed the frequency of loci deletions across the 3p arm separately in HPV-positive and -negative disease. We found that deletions on chromosome 3p were almost exclusively an all or none event in the HPV-negative cohort; patients either had <1% or >97% of the arm deleted. 3p arm loss, defined as >97% deletion in HPV-positive patients and >50% in HPV-negative patients, had no impact on survival (p > 0.05). However, HPV-negative tumors with 3p arm loss presented at a higher N-category and overall stage and developed more distant metastases (p < 0.05). They were enriched for SNVs in TP53, and depleted for point mutations in CASP8, HRAS, HLA-A, HUWE1, HLA-B, and COL22A1 (false discovery rate, FDR < 0.05). 3p arm loss was associated with CNAs across the whole genome (FDR < 0.1), and pathway analysis revealed low lymphoid–non-lymphoid cell interactions and cytokine signaling (FDR < 0.1). In the tumor microenvironment, 3p arm lost tumors had low immune cell infiltration (FDR < 0.1) and elevated hypoxia (FDR < 0.1). 3p arm lost tumors had lower abundance of proteins phospho-HER3 and ANXA1, and higher abundance of miRNAs hsa-miR-548k and hsa-miR-421, which were all associated with survival. There were no molecular differences by 3p arm status in HPV-positive patients, at least at our statistical power level. 3p arm loss is largely an all or none phenomenon in HPV-negative disease and does not predict poorer survival from the time of diagnosis in TCGA cohort. However, it produces tumors with distinct molecular characteristics and may represent a clinically useful biomarker to guide treatment decisions for HPV-negative patients.

【 授权许可】

Unknown