Integrative Analysis of Germline Rare Variants in Clear and Non-clear Cell Renal Cell Carcinoma.

CHEK2-associated cancer risk Copy number variant Cryptic splice variant Germline pathogenic variants Population stratification Renal cell carcinoma

Journal

European urology open science
ISSN: 2666-1683
Titre abrégé: Eur Urol Open Sci
Pays: Netherlands
ID NLM: 101771568

Informations de publication

Date de publication:
Apr 2024
Historique:
accepted: 12 02 2024
medline: 18 3 2024
pubmed: 18 3 2024
entrez: 18 3 2024
Statut: epublish

Résumé

Previous germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types. We first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events. Clear cell RCC patients ( This analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of In this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as

Sections du résumé

Background and objective UNASSIGNED
Previous germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types.
Methods UNASSIGNED
We first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events.
Key findings and limitations UNASSIGNED
Clear cell RCC patients (
Conclusions and clinical implications UNASSIGNED
This analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of
Patient summary UNASSIGNED
In this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as

Identifiants

DOI: 10.1016/j.euros.2024.02.006 PMID: 38496821 PMC: PMC10940785
pubmed: 38496821
doi: 10.1016/j.euros.2024.02.006
pii: S2666-1683(24)00263-5
pmc: PMC10940785
doi:

Types de publication

Journal Article

Langues

eng

Pagination

107-122

Informations de copyright

© 2024 The Author(s).

Auteurs

Seung Hun Han (SH)

Ph.D. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Sabrina Y Camp (SY)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Hoyin Chu (H)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Ryan Collins (R)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.

Riaz Gillani (R)

Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Boston Children's Hospital, Boston, MA, USA.

Jihye Park (J)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Ziad Bakouny (Z)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Cora A Ricker (CA)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Brendan Reardon (B)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Nicholas Moore (N)

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.

Eric Kofman (E)

Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.

Chris Labaki (C)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

David Braun (D)

Center of Molecular and Cellular Oncology, Yale School of Medicine, New Haven, CT, USA.

Toni K Choueiri (TK)

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Brigham and Women's Hospital, Boston, MA, USA.

Saud H AlDubayan (SH)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

Eliezer M Van Allen (EM)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.

Classifications MeSH