Abstract 1755: Integrative genomic and transcriptomic profiles from a prospective cervical cancer study (RAIDs)
Authors: Kamal Maud , Barraud Solenn , Lecompte Lolita , Halladjian Maral , Jeannot Emmanuelle , Girard Elodie , Baulande Sylvain , Legoix Patricia , Lecuru Fabrice , Pauly Léa , Saint-Ghislain Mathilde , Cyrille Stacy , Dupain Célia , Lamy Constance , Chouchane-Mlik Olfa , Oniga Alexandra , Mittelbronn Michel , Tourneau Christophe Le , Latouche Aurélien , Servant Nicolas , Scholl Suzy , Bièche Ivan 
Published: March 2024

Background: Cervical cancer (CC) remains a leading cause of gynecological cancer related mortality worldwide and constitutes the third most common malignancy in women. We have previously reported a “metagene” of genomic markers in the PI3K pathway and epigenetic regulators associated with poor outcome. Immune therapy recently showed promising results yet new biomarkers for targeted therapeutic approaches in this type of cancer remain to be determined.

Patients & Methods: Patients included in this study were enrolled in BioRAIDs [NCT02428842]. Whole exome sequencing (WES), shallow whole genome sequencing (sWGS) and RNA sequencing were performed on quality-controlled primary frozen tumor samples in 297, 306 and 280 patients, respectively who subsequently had received primary radio chemotherapy. Multi-omics bioinformatics analyses were performed to identify alterations representing new valid drug targets in CC. Tumor-stromal characteristics such as transcriptome deconvolution, CD8+, CD45+, CD68+ staining cells, PD-L1 expression, tumor infiltrating lymphocytes (TILs) together with the degree of tumor necrosis were assessed.

Results: 273/306 were HPV positive (89%). Most frequently altered (≥10%) oncogenes were PIK3CA (30%) and TERT promoter (14%). Most frequently altered (≥10%) tumor suppressor genes were FBXW7 (14%), KMT2D (11%), KMT2C (11%) and FAT1 (11%).Microsatellite instability (MSI) was detected in 8/297 (3%) patients, homologous recombination deficiency (HRD)-high status in 8/297 (3%) patients and TMB-high (&gt;10mut/Mb) in 32/297 (11%) patients. The most frequent mutational signatures were APOBEC, deaminase and MMR (DNA mismatch repair deficiency (74%, 28% and 11% respectively). Interestingly, FGFR3 fusions were detected in 8/297 patients (3%). Transcriptomic analyses showed 510 differentially expressed genes between HPV positive and HPV negative CC (adjusted p-value&lt;0.01 and |log2FC|&gt;1). No significantly differentially expressed genes were detected between FIGO 2018 stages (I/II vs III-IV). Both stages as well as tumor necrosis were highly significantly associated with progression-free survival (PFS), with tumor necrosis as an independent prognostic factor in a multivariable analysis (p&lt;0.001).Presence or absence of CD8-positive lymphocytes, or CD68-positive cells of the myeloid cell compartment, histopathological subtype or number of TILs did not correlate with PFS.

Conclusion: Our results confirm the high level of altered genes involved in chromatin remodeling with or without PI3K pathway mutations suggesting the relevance of epidrugs in CC. FGFR3 fusions and HRD tumors - although being rare (3%) - to be considered as new targeted approaches. Additionally, MSI and TMB high are of interest for immunotherapy beyond PD-L1 expression. Integrative analyses of omics and pathology data and correlation with PFS are ongoing and will be presented in the meeting.

Citation Format: Maud Kamal, Solenn Barraud, Lolita Lecompte, Maral Halladjian, Emmanuelle Jeannot, Elodie Girard, Sylvain Baulande, Patricia Legoix, Fabrice Lecuru, Léa Pauly, Mathilde Saint-Ghislain, Stacy Cyrille, Célia Dupain, Constance Lamy, Olfa Chouchane-Mlik, Alexandra Oniga, Michel Mittelbronn, Christophe Le Tourneau, Aurélien Latouche, Nicolas Servant, Suzy Scholl, Ivan Bièche. Integrative genomic and transcriptomic profiles from a prospective cervical cancer study (RAIDs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1755.