Epithelial stem cell marker LGR6 expression identifies a low-risk subgroup in human papillomavirus positive oropharyngeal squamous cell carcinoma

Oral Oncol. 2020 Jun:105:104657. doi: 10.1016/j.oraloncology.2020.104657. Epub 2020 Mar 31.


Objectives: R-Spondins (RSPOs) and leucine-rich repeat-containing G-protein coupled receptors (LGRs) play a critical role in embryonic and cancer development through potentiation of WNT/ß-catenin signaling, but their prognostic significance in head and neck squamous cell carcinoma (HNSCC) is still unclear. HNSCC is a group of neoplasms that include, amongst others, oropharyngeal squamous cell carcinoma (OPSCC), some of which are induced by human papillomavirus (HPV). We aimed to investigate the potential prognostic value of RSPO2 and LGR4/5/6 on overall survival (OS) and disease-free survival (DFS) in HNSCC patients.

Methods: We examined RSPO and LGR expression by means of immunohistochemistry in 126 HNSCC patients. Furthermore, in order to validate our findings externally, we examined RSPO2 and LGR6 mRNA expression levels using independent secondary datasets.

Results: The five-year OS of our cohort was 59.6%. RSPO2 and LGR4/5/6 expression were not associated with OS or DFS in multivariable analyses. Within the HPV+ cases (n = 26, 33%), however, we observed a difference in OS by RSPO2 expression (5-year OS: RSPO+ 45.4% vs. RSPO2- 84.6%) and LGR6 expression (5-year OS: LGR6+ 52.9% vs. LGR6-100%). Evidence for an interaction of HPV status with RSPO2 and LGR6 was found for OS. Relative to HPV+/LGR6- patients, HPV+/LGR6+ patients were 12 times more likely to die. These results were replicated in the second dataset.

Conclusion: Our results indicated that the expression status of LGR6 had an influence on the aggressiveness of HPV+ OPSCC, potentially making this receptor a useful marker for identifying patients with a high risk of death.

Keywords: Head and neck squamous cell carcinoma; Human papillomavirus; Precision medicine; Stem cell marker; Survival.

MeSH terms

  • Aged
  • Cohort Studies
  • Disease-Free Survival
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Oropharyngeal Neoplasms / genetics
  • Oropharyngeal Neoplasms / metabolism*
  • Oropharyngeal Neoplasms / pathology
  • Oropharyngeal Neoplasms / virology*
  • Papillomaviridae / isolation & purification
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / metabolism*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology
  • Precision Medicine / methods
  • Receptors, G-Protein-Coupled / biosynthesis*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Retrospective Studies


  • LGR6 protein, human
  • Receptors, G-Protein-Coupled