Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer
Torres-Esquius, Sara (Vall d'Hebron Institut d'Oncologia)
Llop-Guevara, Alba (Astra Zeneca)
Gutiérrez-Enríquez, Sara (Vall d'Hebron Institut d'Oncologia)
Romey, Marcel (Universitätsklinikum Marburg)
Teule, Alex (Hospital Universitari de Bellvitge)
Llort, Gemma (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Herrero, Ana (Hospital Universitario Miguel Servet (Saragossa))
Sánchez-Henarejos, Pilar (Hospital Clínico Universitario Virgen de la Arrixaca (El Palmar, Múrcia))
Vallmajó, Anna (Hospital Universitari Arnau de Vilanova)
González-Santiago, Santiago (Hospital San Pedro de Alcántara)
Chirivella, Isabel (Hospital Clínic Universitari (València))
Cano, Juana María (Hospital General Universitario de Ciudad Real)
Graña, Begoña (Xerencia de Xestión Integrada de A Coruña)
Simonetti, Sara (Vall d'Hebron Institut d'Oncologia)
Díaz de Corcuera, Isabel (Hospital Universitario de Galdakao)
Ramon y Cajal, Teresa (Institut de Recerca Sant Pau)
Sanz, Judit (Althaia Xarxa Assistencial Universitària de Manresa)
Serrano, Sara (Hospital Universitari Sant Joan de Reus (Tarragona))
Otero, Andrea (IMOMA)
Churruca, Cristina (Hospital de Donostia (Sant Sebastià, País Basc))
Sánchez-Heras, Ana Beatriz (Hospital General Universitario de Elche)
Servitja, Sonia (Hospital del Mar (Barcelona, Catalunya))
Guillén-Ponce, Carmen (Hospital Universitario Ramón y Cajal (IRYCIS))
Brunet, Joan (Institut d'Investigació Biomèdica (Girona))
Denkert, Carsten (Universitätsklinikum Marburg)
Serra, Violeta (Vall d'Hebron Institut d'Oncologia)
Balmaña Gelpí, Judith (Vall d'Hebron Institut d'Oncologia)
Universitat Autònoma de Barcelona

Fecha:	2024
Resumen:	IMPORTANCE RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival. OBJECTIVE To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023. MAIN OUTCOMES AND MEASURES Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test. RESULTS A total of 9507 index patients were reviewed, and 91 patients (1. 0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86. 7%) were women and 181 (55. 8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c. 1026+5_1026+7del (11 of 56 [19. 6%]) and c. 709C>T (9 of 56 [16. 1%]) in RAD51C and c. 694C>T (20 of 35 [57. 1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55. 2% (16 of 29) and 61. 1% (11 of 18) for RAD51C, respectively, and 66. 7% (6 of 9) and 90. 0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD. CONCLUSIONS AND RELEVANCE In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.
Ayudas:	Instituto de Salud Carlos III PI19/01303 Instituto de Salud Carlos III PI22/01200 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01112
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Adult ; Aged ; Breast Neoplasms ; DNA-Binding Proteins ; Female ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Homologous Recombination ; Humans ; Middle Aged ; Ovarian Neoplasms ; Prevalence ; Retrospective Studies ; Spain
Publicado en:	JAMA network open, Vol. 7 Núm. 4 (april 2024) , p. e247811, ISSN 2574-3805

DOI: 10.1001/jamanetworkopen.2024.7811
PMID: 38648056

14 p, 1.1 MB

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