Complex landscape of somatic copy number alterations in head and neck paragangliomas

Copy number alterations (CNAs) drive cancer by amplifying oncogenes and deleting tumor suppressor genes. Although CNA patterns are well-studied in common cancers, they remain poorly characterized in rare tumors.

In this study, we employed an allele-specific copy number analysis using ASCAT on 25 head and neck paragangliomas (HNPGLs) with high tumor cell purity (≥70%) and available clinicopathologic and mutation data.

The majority of HNPGLs exhibited a near-diploid state. The recurrent somatic CNAs were predominantly hemizygous deletions, frequently affecting chromosomal regions 7q11, 1p36, 1p34, and 1p21.1-1p13.2, and involving key tumor suppressor genes associated with paragangliomas/pheochromocytomas (PPGLs), including SDHB, SDHD, ATRX, SDHAF2, FH, MEN1, SDHA, and VHL. Frequent homozygous and hemizygous deletions were also observed in the tumor suppressor genes BCL10, PHF6, RPL5, and STAG2. Whole-gene amplifications were identified in several PPGL-associated oncogenes, such as BRAF, IDH1, PDGFRA, and KIT. Additionally, we identified concurrent mutations and allelic imbalances, suggestive of potential wild type allele loss in several novel tumor suppressor genes (CARS and PRDM2), which may point to a role in tumor pathogenesis.

Collectively, our study reveals a complex landscape of somatic CNAs in HNPGLs. The presence of recurrent alterations in hotspot genomic loci and PPGLs-associated genes suggests that genomic instability may be a significant contributing factor to tumor development and progression.