IDENTIFICATION OF PHARMACOLOGICALLY RELEVANT MUTATIONS IN ENDOMETRIAL CANCER BY WHOLE-EXOME SEQUENCING OF FFPE TUMOUR SAMPLES

Endometrial cancer is a prevalent gynaecologic cancer, but it is far from being homogeneous.It shows an exceptionally diverse genetic background and requires highly personalised treatment plans.In this study, we performed whole-exome sequencing (WES) on formalin-fixed, paraffin-embedded (FFPE) tumour samples from 13 patients with histologically confirmed endometrial cancer in order to identify pharmacologically relevant mutations.This study focused on oncogenic and tumoursuppressor gene mutations that novel therapies might target.Variants in the PIK3CA, PTEN, KRAS, ARID1A, TP53 and mismatch repair genes (MLH1 and MSH2) were interesting.We identified 352 unique variants, with significant mutations observed in PIK3CA (8 patients), PTEN (6 patients), KRAS (4 patients) and ARID1A (5 patients).The mutations were classified as either pathogenic or likely pathogenic.These could be potential targets for existing or experimental therapies.We have found several mutations, possibly actionable by drugs like PI3K inhibitors, mTOR inhibitors and immune checkpoint inhibitors.This research demonstrates the massive potential of WES to reveal the genetic background of endometrial cancer that could help clinicians refine and personalise the treatment options of these patients. RezumatCancerul endometrial este o malignitate ginecologic frecvent, dar este departe de a avea un profil omogen.Prezint un bagaj genetic excepional de divers i necesit planuri de tratament personalizate.n acest studiu, am utilizat secvenierea ntregului exom (WES) pe probe de tumor fixate n formol, ncorporate n parafin (FFPE) de la 13 paciente cu cancer endometrial confirmat histologic pentru a identifica mutaii relevante farmacologic.Analiza a vizat oncogene cheie i gene supresoare tumorale care ar putea fi vizate de terapii noi.Variante din genele PIK3CA, PTEN, KRAS, ARID1A, TP53 i repararea nepotrivirii (MLH1 i MSH2) au fost de interes.Am identificat 352 de variante unice, cu mutaii semnificative observate n PIK3CA (8 paciente), PTEN (6 paciente), KRAS (4 paciente) i ARID1A (5 paciente).Mutaiile au fost clasificate fie ca fiind patogene sau probabil patogene.Acestea ar putea fi inte poteniale pentru terapiile existente sau experimentale.Am identificat mai multe mutaii posibil acionabile de medicamente precum inhibitorii PI3K, inhibitorii mTOR i inhibitorii punctelor de control imun.Aceast cercetare demonstreaz potenialul masiv al WES de a dezvlui bagajul genetic al cancerului endometrial care ar putea ajuta clinicienii s perfecioneze i s personalizeze opiunile de tratament ale acestor paciente.