Trans-ethnic variation in germline variants of patients with renal cell carcinoma

Sarah Abou Alaiwi; Amin H Nassar; Elio Adib; Stefan M Groha; Elie W Akl; Bradley A McGregor; Edward D Esplin; Shan Yang; Kathryn Hatchell; Vincent Fusaro; Sarah Nielsen; David J Kwiatkowski; Guru P Sonpavde; Mark Pomerantz; Judy E Garber; Matthew L Freedman; Huma Q Rana; Alexander Gusev; Toni K Choueiri

doi:10.1016/j.celrep.2021.108926

Trans-ethnic variation in germline variants of patients with renal cell carcinoma

Cell Rep. 2021 Mar 30;34(13):108926. doi: 10.1016/j.celrep.2021.108926.

Authors

Sarah Abou Alaiwi¹, Amin H Nassar², Elio Adib², Stefan M Groha³, Elie W Akl⁴, Bradley A McGregor¹, Edward D Esplin⁵, Shan Yang⁵, Kathryn Hatchell⁵, Vincent Fusaro⁵, Sarah Nielsen⁵, David J Kwiatkowski², Guru P Sonpavde¹, Mark Pomerantz¹, Judy E Garber⁶, Matthew L Freedman⁷, Huma Q Rana⁶, Alexander Gusev³, Toni K Choueiri⁸

Affiliations

¹ Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine and Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ Division of Pulmonary and Critical Care Medicine and Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Invitae Corporation, San Francisco, CA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Population Sciences, Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁸ Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine and Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: toni_choueiri@dfci.harvard.edu.

PMID: 33789101
DOI: 10.1016/j.celrep.2021.108926

Abstract

Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.

Keywords: Ancestry; DNA damage repair; clinical genetics; germline variants; kidney cancer; renal cell carcinoma.

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Carcinoma, Renal Cell / genetics*
Checkpoint Kinase 2 / genetics
Child
Child, Preschool
Ethnicity / genetics*
Female
Genealogy and Heraldry
Genes, Neoplasm
Genetic Association Studies
Genetic Predisposition to Disease
Germ-Line Mutation / genetics*
Humans
Kidney Neoplasms / genetics
Male
Middle Aged
Penetrance
Young Adult

Substances

Checkpoint Kinase 2
CHEK2 protein, human