Molecular landscape of vulvovaginal squamous cell carcinoma: New insights into molecular mechanisms of HPV-associated and HPV-independent squamous cell carcinoma Journal Article
| Authors: | Salama, A. M.; Momeni-Boroujeni, A.; Vanderbilt, C.; Ladanyi, M.; Soslow, R. |
| Article Title: | Molecular landscape of vulvovaginal squamous cell carcinoma: New insights into molecular mechanisms of HPV-associated and HPV-independent squamous cell carcinoma |
| Abstract: | Squamous cell carcinomas of the lower female genital tract may be human papillomavirus-associated or independent. We studied the HPV status, mutational repertoire, histology, and clinical data of 28 samples from 26 patients, 65% with a vulvar primary and 35% with a vaginal primary. These represented invasive vulvovaginal squamous cell carcinomas that underwent clinical tumor-normal targeted massively parallel sequencing analysis. HPV status was determined using the HPV high-risk RNA ISH assay and/or by MSK-IMPACT. Eleven patients had HPV-associated squamous cell carcinoma (four vulvar and seven vaginal) and 15 patients had HPV-independent SqCC (13 vulvar and 2 vaginal). Well-differentiated squamous cell carcinomas were always HPV-independent. HPV-independent moderately and poorly differentiated carcinomas frequently had alterations in the NOTCH signaling pathway (6/7), which were also associated with increased tumor budding (P: 0.002). HPV-associated vulvovaginal squamous cell carcinoma had PIK3CA activating mutations (7/11, 64%) as the most common genomic event, while TERT gene alterations, mainly TERT promoter mutations (14/15 cases, 93%) featured significantly in HPV-independent carcinomas. Other common abnormalities in HPV-independent tumors were TP53 mutations (13/15, 87%), CDKN2A alterations (10/15, 67%), and NOTCH1 and FAT1 mutations (7/15, 47% each). A subset of both HPV-associated and -independent tumors had NOTCH pathway alterations (6/11, 55% and 10/15, 67% respectively), but different genes in this pathway were altered in these tumors. In summary, TERT, TP53, CDKN2A, and NOTCH1 gene alterations strongly point away from an HPV-driven process (odds ratios: 0.01, 0.07, 0, and 0, respectively with p values < 0.02 for all four genes), while PIK3CA activating mutations without the other mutations strongly favors an HPV-driven tumor (odds ratio: 10.12, p value: 0.016). HPV-independent carcinomas are more likely to be moderately-poorly differentiated with intermediate to high tumor cell budding. Cancer cell fraction analysis of HPV-independent squamous carcinomas suggests that TERT and/or NOTCH1 alterations along with TP53 alterations can be the initiating event in these tumors. © 2021, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology. |
| Keywords: | immunohistochemistry; adult; cancer chemotherapy; clinical article; human tissue; aged; unclassified drug; oncoprotein; gene mutation; human cell; overall survival; promoter region; somatic mutation; gene deletion; histopathology; cancer recurrence; squamous cell carcinoma; cancer growth; cancer radiotherapy; disease free survival; cancer staging; follow up; progression free survival; cohort analysis; genetic association; notch receptor; cell differentiation; enzyme activation; phosphatidylinositol 3 kinase; protein p53; cancer mortality; distant metastasis; risk assessment; cancer specific survival; histone h3; cancer cell; cancer size; telomerase reverse transcriptase; cell fractionation; cyclin dependent kinase inhibitor 2a; gene dosage; codon; cell cycle regulation; local metastasis; infection risk; virus detection; vulva carcinoma; notch1 receptor; vagina carcinoma; ephrin receptor b1; platelet derived growth factor beta receptor; virus dna; molecular pathology; rna analysis; female genital tract cancer; papillomavirus infection; intraepithelial neoplasia; protein asxl1; tumor invasion; clonal evolution; cell budding; notch signaling; cyclic amp responsive element binding protein binding protein; depth of invasion; cancer prognosis; massively parallel signature sequencing; human; female; article; vulvovaginal disease; median survival time; protein fat1; lichen sclerosus et atrophicus; protein bap1; f box/wd repeat containing protein 7; protein kmt2d; protein spen; receptor interacting protein 140; alphapapillomavirus 2 |
| Journal Title: | Modern Pathology |
| Volume: | 35 |
| Issue: | 2 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2022-02-01 |
| Start Page: | 274 |
| End Page: | 282 |
| Language: | English |
| DOI: | 10.1038/s41379-021-00942-3 |
| PUBMED: | 34650187 |
| PROVIDER: | scopus |
| PMCID: | PMC9450957 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2022 -- Source: Scopus |
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1330Ladanyi -
797Soslow -
138Vanderbilt -
16Salama
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