Jean-François Vanbellinghen

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

Abstract Introduction: Homologous Recombination Repair (HRR) pathway repairs DNA double-strand breaks. Loss of HRR capability is known to lead to genomic instability resulting in a phenotype called Homologous Recombination Deficiency (HRD). The utility of HRD biomarker in cancer treatment lies in its ability to predict response to specific types of therapy such as platinum-based chemotherapy and PARP inhibitors (PARPi). HRD tests evaluating scores of allelic imbalances, such as genomic scar (GS) or loss of heterozygosity (LOH), have been shown to identify a subgroup of BRCA wild-type (wt) tumors showing a HRD phenotype. Currently, HRD status is being used as a biomarker in cancer profiling, helping clinicians determine the best treatment option for their patients. In this perspective, OncoDNA® has developed a pan-cancer tumor profiling solution, the OncoDEEP® kit, facilitating the genomic analysis of both tumor DNA and RNA, and supported with Bio-IT analysis and clinical reporting. This end-to-end solution screens for a very wide range of cancer biomarkers and genomic signatures such as HRD. Hence, the OncoDEEP® kit can aid in reducing the costs of testing and deliver faster results for the selection of appropriate cancer treatment. Methods: OncoDEEP® kit, based on Twist technology, was performed at OncoDNA laboratory facilities on 246 extracted DNA from FFPE ovarian carcinoma of the PAOLA-1/ENGOT-ov25 cohort. Those samples were previously characterized with Myriad Mychoice DX and obtained at Arcagy Gineco®. Sequencing was performed on Illumina Novaseq X. All 638 genes on OncoDEEP® panel, inclusive of BRCA1/2 and other HRR genes, were analyzed via OncoDNA proprietary bioIT pipeline and GS was calculated using Loss of Heterozygosity (LOH), Allelic Disparity on Telomere (ADT) and Large-scale Rearrangements (LR), with a positive threshold of 37. Afterwards, results were matched with PFS and treatment. Results: HRD analysis of OncoDEEP® showed a high correlation with Myriad MyChoice DX, with an overall concordance of 85 %. In addition, OncoDEEP showed to be highly predictive (p-value≤0.001) of tumor response to olaparib+bevacizumab. Tumors harboring a positive HRD phenotype and treated with olaparib+bevacizumab exhibited a median PFS of 36.4 months, while median PFS of placebo-treated tumors was 18.75 months. Finally, OncoDEEP analysis presented a lower failure rate (0.8%) compared to Myriad MyChoice Dx (6.5%). Conclusion: OncoDEEP® kit is an end-to-end solution allowing the detection of variants in 638 genes and the calculation of genomic signatures such as TMB, MSI and HRD. OncoDEEP® HRD analysis showed to be highly predictive of tumor response treated by olaparib+bevacizumab and is therefore applicable to the identification of ovarian cancer patients eligible to PARPi therapy in oncology routine. Citation Format: Marcel Trautmann, Simon Lefèvre, Sébastien Sauvage, Jessie Hong, Maxime Liénard, Karim Ashour Garrido, Jean-François Vanbellinghen, Rapahël Léonard. Clinical validation on the PAOLA-1/ENGOT-ov25 cohort of HRD calculation performed with the OncoDEEP® kit comprehensive genomic panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1492.