Laura Mezquita1, Maria Jové2, Ernest Nadal2, Maria Kfoury3, Teresa Morán4, Charles Ricordel5, Marion Dhooge6, Camille Tlemsani7, Hervé Léna5, Alex Teulé2, Jose-Valero Álvarez8, Judith Raimbourg9, Sandrine Hiret9, Ludovic Lacroix10, Mireia Menéndez11, Juana Saldaña2, Joan Brunet4, Pilar Lianes12, Isabelle Coupier13, Edouard Auclin14, Gonzalo Recondo15, Luc Friboulet15, Julien Adam16, Emma Green17, David Planchard3, Thierry Frébourg18, Gabriel Capellà11, Etienne Rouleau10, Conxi Lázaro11, Olivier Caron19, Benjamin Besse20. 1. Thoracic Oncology Group, Cancer Medicine Department, Gustave Roussy, Villejuif, France; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain. 2. Medical Oncology Department, Catalan Institute of Oncology (ICO-IDIBELL-ONCOBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 3. Thoracic Oncology Group, Cancer Medicine Department, Gustave Roussy, Villejuif, France. 4. Medical Oncology Department, Catalan Institute of Oncology-Badalona (ICO-Badalona), Institut Germans Trias i Pujol (IGTP), Badalona Applied Research Group in Oncology (B-ARGO), Universitat Autònoma de Barcelona (UAB), Medicine Department, Badalona, Spain. 5. Department of Respiratory Medicine, Pontchaillou Hospital, Rennes, France; University of Rennes, Rennes, France; Chemistry, Oncogenesis, and Stress Signaling, INSERM, Centre Eugène Marquis, Rennes, France. 6. Gastroenterology Department, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 7. Medical Oncology Department, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Cancer Research for PErsonalized Medicine (CARPEM), Paris, France; Paris Descartes University, USPC, Paris, France. 8. Medical Oncology Department, Complejo Hospitalario de Zamora, Hospital Provincial, Zamora, Spain. 9. Medical Oncology Department, Institute de Cancerologie de l'Ouest, Nantes, France. 10. Medical Biology and Pathology Department, Translational Research Laboratory and BioBank, Gustave Roussy, Villejuif, France. 11. Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL-ONCOBELL-CIBERONC), L'Hospitalet de Llobregat, Barcelona, Spain. 12. Medical Oncology Department, Hospital de Mataró, Mataró, Spain. 13. Clinical Genetic Unit, Montpeiller Cancer Institut, CHU Montpellier, Montpeiller, France. 14. Gastrointestinal and Medical Oncology Department, Hôpital Européen Georges Pompidou, Paris, France. 15. INSERM, Gustave Roussy Cancer Campus, Université Paris Saclay, Saint-Aubin, France. 16. Pathology Department, Gustave Roussy, Villejuif, France. 17. Inivata Ltd., Cambridge, United Kingdom. 18. Normandie Univ, UNIROUEN, INSERM, and Rouen University Hospital, Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Rouen, France. 19. Clinical Genetic Unit, Cancer Medicine Department, Gustave Roussy, Villejuif, France. Electronic address: olivier.caron@gustaveroussy.fr. 20. Thoracic Oncology Group, Cancer Medicine Department, Gustave Roussy, Villejuif, France; INSERM, Gustave Roussy Cancer Campus, Université Paris Saclay, Saint-Aubin, France.
Abstract
INTRODUCTION: Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown. METHODS: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants. RESULTS: Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation. CONCLUSIONS: Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.
INTRODUCTION: Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown. METHODS: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants. RESULTS: Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation. CONCLUSIONS: Driver oncogenic alterations were observed in 90% of the LFStumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.
Authors: Igor Araujo Vieira; Tiago Finger Andreis; Bruna Vieira Fernandes; Maria Isabel Achatz; Gabriel S Macedo; Daniel Schramek; Patricia Ashton-Prolla Journal: Front Genet Date: 2021-02-02 Impact factor: 4.599
Authors: Shelby Edmondson; Mitchell S von Itzstein; Brian Reys; Melissa Mayer; Jeffrey Gagan; David E Gerber Journal: JTO Clin Res Rep Date: 2022-06-25