Germline variants in DNA repair genes are associated with young-onset head and neck cancer

Author(s)

Cury, Sarah Santiloni ^{[1, 2]} ; de Miranda, Priscila Mayrink ^[3] ; Marchi, Fabio Albuquerque ^[3] ; do Canto, Luisa Matos ^[1] ; Chulam, Thiago Celestino ^[4] ; Petersen, Annabeth Hogh ^[1] ; Aagaard, Mads M. ^[1] ; Pinto, Clovis Antonio Lopes ^[5] ; Kowalski, Luiz Paulo ^[4] ; Rogatto, Silvia Regina ^[1]

Affiliation

^[1] Univ Southern Denmark, Dept Clin Genet, Univ Hosp Southern Denmark, Inst Reg Hlth Res, Odense - Denmark

^[2] Sao Paulo State Univ UNESP, Dept Struct & Funct Biol, Botucatu, SP - Brazil

^[3] CIPE AC Camargo Canc Ctr, Int Res Ctr, Sao Paulo - Brazil

^[4] AC Camargo Canc Ctr, Dept Head & Neck Surg & Otorhinolaryngol, Sao Paulo - Brazil

^[5] AC Camargo Canc Ctr, Dept Pathol, Sao Paulo - Brazil

• Document type: Journal article
• Source: Oral Oncology; v. 122, NOV 2021.
• Web of Science Citations: 0

Abstract

The genetic predisposition to head and neck carcinomas (HNSCC) and how the known risk factors (papillomavirus infection, alcohol, and tobacco consumption) contribute to the early-onset disease are barely explored. Although HNSCC at early onset is rare, its frequency is increasing in recent years. Germline and somatic variants were assessed to build a comprehensive genetic influence pattern in HNSCC predisposition and patient outcome. Whole-exome sequencing was performed in 45 oral and oropharynx carcinomas paired with normal samples of young adults (<= 49 years). We found FANCG, CDKN2A, and TPP germline variants previously associated with HNSCC risk. At least one germline variant in DNA repair pathway genes was detected in 67% of cases. Germline and somatic variants (including copy number variations) in FATI gene were identified in 9 patients (20%) and 12 tumors (30%), respectively. Somatic variants were found in HNSCC associated genes, such as TP53, CDKN2A, and PIK3CA. To date, 55 of 521 cases from the large cohort of TCGA presented < 49 years old. A comparison between the somatic alterations of TCGA-HNSCC at early onset and our dataset revealed strong similarities. Protein-protein interaction analysis between somatic and germline altered genes revealed a central role of TP53. Altogether, germline alterations in DNA repair genes potentially contribute to an increased risk of developing HNSCC at early-onset, while FATI could impact the prognosis. (AU)

• FAPESP's process: 08/57887-9 - National Institute of Oncogenomics
• Grantee: Luiz Paulo Kowalski
• Support Opportunities: Research Projects - Thematic Grants