Synapse - Molecular and microenvironmental landscapes of human papillomavirus-independent invasive squamous cell carcinoma of the vulva

Molecular and microenvironmental landscapes of human papillomavirus-independent invasive squamous cell carcinoma of the vulva Journal Article

Authors:	Moufarrij, S.; Filippova, O.; Da Cruz Paula, A.; Heredia, J. B.; Green, H.; Broach, V.; Leitao, M. M. Jr; O'Cearbhaill, R. E.; Abu-Rustum, N. R.; Park, K. J.; Weigelt, B.; Zamarin, D.
Article Title:	Molecular and microenvironmental landscapes of human papillomavirus-independent invasive squamous cell carcinoma of the vulva
Abstract:	Objective: Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma has a worse prognosis compared to its HPV-associated counterpart. We sought to characterize the mutational landscape and the tumor microenvironment of HPV-independent vulvar cancer. Methods: Primary, untreated vulvar cancers with known HPV-independent vulvar cancer or without definitive HPV association between 2006 and 2016 were identified. Pathology re-review, p16 immunohistochemistry, and HPV 16 and 18 polymerase chain reaction were performed to determine HPV status. HPV-independent vulvar cancers underwent targeted tumor-normal panel sequencing and NanoString gene expression analysis. Multiplex immunofluorescence analysis for CD8, programmed cell death protein-1, and PD-L1 was performed for HPV-independent and HPV-associated vulvar squamous cell carcinomas. Results: Of the 93 vulvar squamous cell carcinomas identified, 19 were HPV-independent. Targeted sequencing revealed recurrent somatic mutations affecting TP53 (13/19, 68%), FAT1 (6/19, 32%), NOTCH1 (5/19, 26%), and CDKN2A (5/19, 26%). Five (26%) of the 19 cases had a dominant apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-related mutational signature, whereas the remaining had dominant clock/aging-related mutational signatures. Expression of genes related to immune response including the chemokine CXCL8 and HLA-DRB5 were found to be significantly higher in primary HPV-independent vulvar squamous cell carcinomas that did not recur compared to those with subsequent recurrence (p = .02). Multiplex immunofluorescence analysis revealed that HPV-independent vulvar squamous cell carcinomas were characterized by tumor infiltration with CD8+programmed cell death protein-1+ T cells and their interaction with CD68+PD-L1+ macrophages. Conclusions: HPV-independent vulvar squamous cell carcinoma is a heterogeneous disease with mutations affecting cell cycle-related genes, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide and clock-like mutational signatures, and evidence of an immune-active tumor microenvironment in primary tumors. Our data provide the basis for exploration of immune biomarkers and therapeutics in this disease. © 2024 European Society of Gynaecological Oncology and the International Gynecologic Cancer Society
Keywords:	immunohistochemistry; adult; controlled study; human tissue; aged; human cell; major clinical study; somatic mutation; antineoplastic agent; polymerase chain reaction; cd8 antigen; cd8+ t lymphocyte; protein p16; progression free survival; gene expression; interleukin 1beta; interleukin 8; cohort analysis; practice guideline; immunofluorescence; retrospective study; protein p53; oncogene h ras; antigen presentation; immune response; recurrent disease; chromosomal instability; upregulation; cyclin dependent kinase inhibitor 2a; gamma interferon inducible protein 10; interleukin 1alpha; interstitial collagenase; neutrophil chemotaxis; vulva carcinoma; notch1 receptor; stromelysin; matrilysin; cd68 antigen; programmed death 1 ligand 1; programmed death 1 receptor; cxcl9 chemokine; tumor microenvironment; vulva cancer; calgranulin a; papillomavirus infection; tp53; human papillomavirus type 16; human papillomavirus type 18; rantes; tumor invasion; cxcl11 chemokine; calgranulin b; cxcl14 chemokine; human; female; article; differential expression analysis; apobec; immune signaling; apolipoprotein b mrna editing enzyme catalytic polypeptide like; immunometabolism; tumor mutational burden; lichen sclerosus et atrophicus; fat1 gene; calgranulin c; vulvar squamous cell carcinoma; hpv-independent vulvar carcinoma; hla drb5 antigen
Journal Title:	International Journal of Gynecological Cancer
Volume:	35
Issue:	2
ISSN:	1048-891X
Publisher:	Lippincott Williams & Wilkins
Date Published:	2025-02-01
Start Page:	100051
Language:	English
DOI:	10.1016/j.ijgc.2024.100051
PROVIDER:	scopus
PUBMED:	39971436
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85218058288&doi=10.1016%2fj.ijgc.2024.100051&partnerID=40&md5=6feb859cb709ba8806bcb085b34b5285
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus