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

Sarah Santiloni Cury, Priscila Mayrink de Miranda, Fabio Albuquerque Marchi, Luisa Matos do Canto, Thiago Celestino Chulam, Annabeth Høgh Petersen, Mads M. Aagaard, Clóvis Antonio Lopes Pinto, Luiz Paulo Kowalski, Silvia Regina Rogatto*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


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 FAT1 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 FAT1 could impact the prognosis.

Original languageEnglish
Article number105545
JournalOral Oncology
Publication statusPublished - Nov 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Ltd


  • Cancer predisposition
  • Early-onset cancer
  • Oral cavity carcinomas
  • Oropharynx carcinomas
  • Risk factors
  • Whole-exome sequencing


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