HPV51-associated Leiomyosarcoma: A Novel Class of TP53/RB1-Wildtype Tumor With Predilection for the Female Lower Reproductive Tract.

Autor:	Williams EA; Departments of Pathology and Dermatology, UCSF Dermatopathology Service, Helen Diller Family Cancer Center, University of California, San Francisco, CA.; Foundation Medicine Inc., Cambridge., Montesion M; Foundation Medicine Inc., Cambridge., Lincoln V; Departments of Pathology and Dermatology, UCSF Dermatopathology Service, Helen Diller Family Cancer Center, University of California, San Francisco, CA., Tse JY; Foundation Medicine Inc., Cambridge., Hiemenz MC; Foundation Medicine Inc., Cambridge., Mata DA; Foundation Medicine Inc., Cambridge., Shah BB; Foundation Medicine Inc., Cambridge., Shoroye A; Foundation Medicine Inc., Cambridge., Alexander BM; Foundation Medicine Inc., Cambridge., Werth AJ; Department of Women's Health Services, Hartford Hospital, Hartford, CT., Foley-Peres K; Department of Biology, Bristol Community College, Fall River, MA., Milante RR; Department of Dermatology, Jose R. Reyes Memorial Medical Center, Manila, Philippines., Ross JS; Foundation Medicine Inc., Cambridge.; Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY., Ramkissoon SH; Foundation Medicine Inc., Cambridge.; Wake Forest Comprehensive Cancer Center and Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC., Williams KJ; Departments of Physiology and Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA., Adhikari LJ; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK., Zuna RE; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK., LeBoit PE; Departments of Pathology and Dermatology, UCSF Dermatopathology Service, Helen Diller Family Cancer Center, University of California, San Francisco, CA., Lin DI; Foundation Medicine Inc., Cambridge., Elvin JA; Foundation Medicine Inc., Cambridge.
Jazyk:	angličtina
Zdroj:	The American journal of surgical pathology [Am J Surg Pathol] 2022 Jun 01; Vol. 46 (6), pp. 729-741. Date of Electronic Publication: 2022 Jan 17.
DOI:	10.1097/PAS.0000000000001862
Abstrakt:	Inactivating mutations in tumor suppressor genes TP53 and RB1 are considered central drivers in leiomyosarcomas (LMSs). In high-risk human papillomavirus (HPV)-related tumors, a similar functional outcome is achieved through oncoproteins E6 and E7, which inactivate the p53 and RB1 proteins, respectively. Here, we hypothesized that HPV infection could provide an alternative mechanism for tumorigenesis in a subset of TP53/RB1-wildtype LMS. We evaluated tumor samples from 2585 consecutive unique patients carrying a diagnosis of gynecologic or soft tissue LMS. Tumor DNA and available RNA were analyzed by hybrid-capture-based next-generation sequencing/comprehensive genomic profiling of 406 genes and transcripts (FoundationOneHeme). Of the initial 2585 cases, we excluded 16 based on the presence of molecular alterations that are considered defining for sarcomas other than LMS. In the remaining 2569 cases, we searched for LMS that were TP53/RB1-wildtype (n=486 of 2569; 18.9%). We also searched LMS tumors for HPV sequences that we then classified into genotypes by de novo assembly of nonhuman sequencing reads followed by alignment to the RefSeq database. Among TP53/RB1-wildtype LMS, we identified 18 unique cases harboring HPV sequences. Surprisingly, most (n=11) were HPV51-positive, and these 11 represented all HPV51-positive tumors in our entire LMS database (n=11 of 2569; 0.4%). The absence of genomic alterations in TP53 or RB1 in HPV51-positive LMS represented a marked difference from HPV51-negative LMS (n=2558; 0% vs. 72% [P<0.00001], 0% vs. 53% [P=0.0002]). In addition, compared with HPV51-negative LMS, HPV51-positive LMS were significantly enriched for genomic alterations in ATRX (55% vs. 24%, P=0.027) and TSC1 (18% vs. 0.6%, P=0.0047). All HPV51-positive LMS were in women; median age was 54 years at surgery (range: 23 to 74 y). All known primary sites were from the gynecologic tract or adjacent anogenital area, including 5 cases of vaginal primary site. Histology was heterogeneous, with evaluable cases showing predominant epithelioid (n=5) and spindle (n=5) morphology. In situ hybridization confirmed the presence of high-risk HPV E6/E7 mRNA in tumor cells in three of three evaluable cases harboring HPV51 genomic sequences. Overall, in our pan-LMS analysis, HPV reads were identified in a subset of TP53/RB1-wildtype LMS. For all HPV51-associated LMS, the striking absence of any detectable TP53 or RB1 mutations and predilection for the female lower reproductive tract supports our hypothesis that high-risk HPV can be an alternative tumorigenic mechanism in this distinct class of LMS. Competing Interests: Conflicts of Interest and Source of Funding: E.A.W., M.M., J.Y.T., M.C.H., D.A.M., B.B.S., B.M.A., J.S.R., S.H.R., D.I.L., and J.A.E. are employees or consultants of Foundation Medicine Inc., a wholly owned subsidiary of Roche Holdings Inc. and Roche Finance Ltd, and these employees have equity interest in an affiliate of these Roche entities. For the remaining authors none were declared. (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)
Databáze:	MEDLINE
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