Novel MSH6 mutation predicted metastasis in eyelid and periocular squamous cell carcinoma

J Eur Acad Dermatol Venereol. 2022 Dec;36(12):2331-2342. doi: 10.1111/jdv.18454. Epub 2022 Aug 23.


Background: Our previous research revealed the relative local aggressiveness of eyelid and periocular squamous cell carcinoma (EPSCC), but its distinct genetic characteristics involved remain unknown.

Objectives: We conducted this study based on next-generation sequencing to identify the genetic distinctiveness of EPSCC and damaging mutations for possible aetiology and poor prognosis.

Methods: We performed sequencing using a 556-gene panel (SmartOnco) in 48 EPSCCs. Cox hazards model was applied to explore mutated genes that increase the risk of metastasis and death. Pathogenesis of the mutations was predicted by sequence alignment algorithms.

Results: The most commonly mutated genes were KMT2C (N = 17, 35%), LRP1B (N = 14, 29%), KMT2D (N = 12, 25%), PTCH1 (N = 10, 21%) and TP53 (N = 10, 21%). DNA mismatch repair (MMR) genes (42%) like MSH6 (19%) and MLH3 (12%) were among the most frequently mutated genes. Cell cycle regulators including TP53 (21%) and CDKN2A (10%) were less frequently mutated than in other squamous cell carcinomas (SCCs). Ultraviolet exposure, MMR deficiency and ageing were the main aetiology. Of note, KMT2C has a deleterious mutation hotspot. Patients burdened with MSH6 mutation has a higher risk of overall metastasis (P = 0.045, HR = 5.165) and nodal metastasis (P = 0.022, HR = 14.038). Moreover, a hotspot mutation MSH6E52A brought an even higher risk of nodal metastasis (P = 0.011, HR = 18.745).

Conclusions: EPSCCs displayed a unique mutation profile from cutaneous SCCs and mucosal SCCs. We have identified novel damaging mutations in epigenetic regulators like KMT2C boosted early onset of EPSCCs in addition to UVR, ageing or MMR deficiency. And malfunction of MMR genes worsened prognosis.

MeSH terms

  • Carcinoma, Squamous Cell* / pathology
  • DNA-Binding Proteins / genetics
  • Eyelids / pathology
  • Humans
  • Mutation


  • DNA-Binding Proteins

Supplementary concepts

  • Turcot syndrome