Genomic characterization of vulvar squamous cell carcinoma.
Adult
Aged
Aged, 80 and over
Carcinoma, Squamous Cell
/ genetics
Case-Control Studies
Female
Humans
Lymphatic Metastasis
Middle Aged
Mutation
Papillomaviridae
/ isolation & purification
Papillomavirus Infections
/ genetics
Tumor Suppressor Protein p53
/ genetics
Vulvar Neoplasms
/ genetics
Exome Sequencing
HPV
Sequencing
TP53
Vulvar cancer
Whole exome
Journal
Gynecologic oncology
ISSN: 1095-6859
Titre abrégé: Gynecol Oncol
Pays: United States
ID NLM: 0365304
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
21
04
2020
accepted:
08
06
2020
pubmed:
28
6
2020
medline:
16
4
2021
entrez:
28
6
2020
Statut:
ppublish
Résumé
Despite increasing incidence, vulvar squamous cell carcinoma (VSCC) is still a rare disease. Until now, two etiological pathways have been described: a high-risk human papillomavirus (HPV)-dependent route and an HPV-independent pathway often associated with lichen sclerosus. To date, therapeutic strategies in VSCC are not influenced by molecular pathological information and therapeutic options for advanced or recurrent disease are limited. Whole exome sequencing of DNA, isolated from 34 VSCC samples and matched normal tissue for each individual was performed on an Illumina HiSeq4000. Short variant discovery was carried out using BWA mem and FreeBayes. Variants were annotated using ANNOVAR. FIGO stages were: IB (n = 7), II (n = 11), III (n = 8), and IVA (n = 3), (n = 5 unknown). TP53 missense mutations were most commonly detected with 56% (19/34). 12/34 (35.3%) samples were HPV positive (all HPV16), HPV positivity and TP53 mutations were mutually exclusive (p < .0001). Additionally, we observed mutations in known cancer relevant genes, like NBPF1 (n = 7), MACF1 (n = 5), SYNE2 (n = 5), DOCK2 (n = 4), KMT2D (n = 4), MAP2 (n = 4), NACA (n = 4), PIK3CA (n = 4), SYNE1 (n = 4), FBWX7 (n = 3), MSH6 (n = 3), NSD1 (n = 3), POLE (n = 3), TSC2, (n = 3) and CDKN2A (n = 2), but at considerably lower frequencies. For the total cohort 1848 cancer related mutations were detected (median of 54.4 per sample). The key mutation in HPV negative vulvar carcinoma affects TP53. While a multitude of cancer related mutations was detected in various samples, only few mutations recur and/or affect concurrent signaling pathways.
Sections du résumé
BACKGROUND
Despite increasing incidence, vulvar squamous cell carcinoma (VSCC) is still a rare disease. Until now, two etiological pathways have been described: a high-risk human papillomavirus (HPV)-dependent route and an HPV-independent pathway often associated with lichen sclerosus. To date, therapeutic strategies in VSCC are not influenced by molecular pathological information and therapeutic options for advanced or recurrent disease are limited.
METHODS
Whole exome sequencing of DNA, isolated from 34 VSCC samples and matched normal tissue for each individual was performed on an Illumina HiSeq4000. Short variant discovery was carried out using BWA mem and FreeBayes. Variants were annotated using ANNOVAR.
RESULTS
FIGO stages were: IB (n = 7), II (n = 11), III (n = 8), and IVA (n = 3), (n = 5 unknown). TP53 missense mutations were most commonly detected with 56% (19/34). 12/34 (35.3%) samples were HPV positive (all HPV16), HPV positivity and TP53 mutations were mutually exclusive (p < .0001). Additionally, we observed mutations in known cancer relevant genes, like NBPF1 (n = 7), MACF1 (n = 5), SYNE2 (n = 5), DOCK2 (n = 4), KMT2D (n = 4), MAP2 (n = 4), NACA (n = 4), PIK3CA (n = 4), SYNE1 (n = 4), FBWX7 (n = 3), MSH6 (n = 3), NSD1 (n = 3), POLE (n = 3), TSC2, (n = 3) and CDKN2A (n = 2), but at considerably lower frequencies. For the total cohort 1848 cancer related mutations were detected (median of 54.4 per sample).
CONCLUSIONS
The key mutation in HPV negative vulvar carcinoma affects TP53. While a multitude of cancer related mutations was detected in various samples, only few mutations recur and/or affect concurrent signaling pathways.
Identifiants
pubmed: 32591094
pii: S0090-8258(20)32297-6
doi: 10.1016/j.ygyno.2020.06.482
pii:
doi:
Substances chimiques
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
547-554Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Prof. Dr. Linn Woelber: Congress fees and reimbursement of travel expenses as well as lecture fees from med update GmbH, medac oncology, promedicis GmbHRoche, Tesaro, TEVA, OmniaMed, Pfizer. Study support (third-party funding) from Greiner, Roche Diagnostics and medac oncology. All other authors declare no conflicts of interest involved with the presented data.