International journal of gynecological cancer : official journal of the International Gynecological Cancer Society · 2024
Molecular and microenvironmental landscapes of human papillomavirus-independent invasive squamous cell carcinoma of the vulva.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Moufarrij Sara, Filippova Olga, Da Cruz Paula Arnaud, Heredia Juan Blanco, Green Hunter, Broach Vance, Leitao Mario M, O'Cearbhaill Roisin E, Abu-Rustum Nadeem R, Park Kay J, Weigelt Britta, Zamarin Dmitriy
Аннотация
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.
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.