Pro-metastatic gene expression, immune evasion and an altered HPV spectrum characterize an aggressive subtype of cervical cancer
Chakravarthy, A.; Henderson, S.; Dong, C.; Kirkwood, N.; Jeyakumar, M.; McDermott, J.; Su, X.; Egawa, N.; Fjeldbo, C. S.; Halle, M. K.; Krakstad, C.; Soleiman, A.; Sprung, S.; Lyng, H.; Fiegl, H.; Salvesen, H.; Doorbar, J.; Chester, K.; Feber, A.; Fenton, T. R.
Show abstract
Human papillomavirus (HPV)-associated cervical cancer represents one of the leading causes of cancer death worldwide. Although low-middle income countries are disproportionately affected, our knowledge of the disease predominantly originates from populations in high-income countries. Using the largest multi-omic analysis of cervical squamous cell carcinoma (CSCC) to date, totalling 643 tumours and representing patient populations from the USA, Europe and Sub-Saharan Africa, we identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 tumours are largely HPV16-driven, display increased cytotoxic T-lymphocyte infiltration and frequently harbour PIK3CA and EP300 mutations. C2 tumours are associated with shorter overall survival, are frequently driven by HPVs from the HPV18-containing alpha-7 clade, harbour alterations in the Hippo signalling pathway and increased expression of immune checkpoint genes, B7-H3 (also known as CD276) and NT5E (also known as CD73) and PD-L2 (also known as PDCD1LG2). In conclusion, we identify two novel, therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.
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