Mutational signatures and mutagenic impacts associated with betel quid chewing in oral squamous cell carcinoma

  • Shih-Chi Su
  • Lun-Ching Chang
  • Chiao-Wen Lin
  • Mu-Kuan Chen
  • Chun-Ping Yu
  • Wen-Hung Chung
  • Shun-Fa YangEmail author
Original Investigation


Betel quid (BQ) chewing is a prevailing risk for oral squamous cell carcinoma (OSCC) in Southeast Asia. Yet, the detailed mechanisms by which BQ chewing damages the genome are still not fully understood. Through exome sequencing of tumor–normal pairs from 196 male patients with OSCC, including 95 habitual BQ chewers and 101 non-BQ users, we conducted a quantitative survey of mutational signatures and genomic aberrations and explored their association with BQ chewing. We found that BQ-associated elevation in mutation rate was seen in cancers of the tongue, but not in overall OSCC. Additionally, we identified a mutational signature that is enriched in tumors from BQ users. Moreover, the numbers of small insertions and deletions (INDELs) and breakpoints derived from structural variations (SV) were increased, whereas the extent of loss of heterozygosity was decreased in BQ-related OSCC genomes. However, neither the number of base substitutions and microsatellite instability events nor the extent of copy-number alterations differed between BQ-related and -unrelated OSCC. In conclusion, consistent with the proposition that BQ chewing increases OSCC risk as a mutagen, our results unveil a BQ-associated mutational signature and indicate mutagenic impacts of BQ chewing on preferentially eliciting INDELs and SV-related breakpoints in OSCC genomes.



This study was supported by research grants from Chung Shan Medical University Hospital, Taiwan (CSH-2019-E-001-Y3) and the Health and Welfare Surcharge on Tobacco Products (grants MOHW107-TDU-B-212-114025; MOHW108-TDU-B-212-124025) from the Ministry of Health and Welfare (MOHW), Executive Yuan, Taiwan to SFY, and from Chang Gung Memorial Hospital (CMRPG2F0421) to SCS. We thank Tissue Bank at Chang Gung Memorial Hospital, Keelung, for sample preparation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the institutional review board of Chung Shan Medical University Hospital, Taichung, Taiwan (CSMUH NO: CS17132), and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

439_2019_2083_MOESM1_ESM.docx (295 kb)
Supplementary material 1 (DOCX 295 kb)
439_2019_2083_MOESM2_ESM.xlsx (266 kb)
Supplementary material 2 (XLSX 266 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Whole-Genome Research Core Laboratory of Human DiseasesChang Gung Memorial HospitalKeelungTaiwan
  2. 2.Department of Dermatology, Drug Hypersensitivity Clinical and Research CenterChang Gung Memorial HospitalLinkouTaiwan
  3. 3.Department of Mathematical SciencesFlorida Atlantic UniversityBoca RatonUSA
  4. 4.Institute of Oral SciencesChung Shan Medical UniversityTaichungTaiwan
  5. 5.Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
  6. 6.Department of Otorhinolaryngology-Head and Neck SurgeryChanghua Christian HospitalChanghuaTaiwan
  7. 7.Biodiversity Research CenterAcademia SinicaTaipeiTaiwan
  8. 8.School of Medicine, College of MedicineChang Gung UniversityTaoyuanTaiwan
  9. 9.Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
  10. 10.Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan

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