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

Seung Hun Han; Sabrina Y Camp; Hoyin Chu; Ryan Collins; Riaz Gillani; Jihye Park; Ziad Bakouny; Cora A Ricker; Brendan Reardon; Nicholas Moore; Eric Kofman; Chris Labaki; David Braun; Toni K Choueiri; Saud H AlDubayan; Eliezer M Van Allen

doi:10.1016/j.euros.2024.02.006

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

Eur Urol Open Sci. 2024 Mar 8:62:107-122. doi: 10.1016/j.euros.2024.02.006. eCollection 2024 Apr.

Authors

Seung Hun Han^{1

2

3}, Sabrina Y Camp^{2

3}, Hoyin Chu^{2

3}, Ryan Collins^{2

3

4}, Riaz Gillani^{3

5

6

7}, Jihye Park^{2

3}, Ziad Bakouny^{2

3}, Cora A Ricker^{2

3}, Brendan Reardon^{2

3}, Nicholas Moore⁸, Eric Kofman⁹, Chris Labaki², David Braun¹⁰, Toni K Choueiri^{11

12}, Saud H AlDubayan^{2

3

13

14}, Eliezer M Van Allen^{2

3

15}

Affiliations

¹ Ph.D. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
³ Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁷ Boston Children's Hospital, Boston, MA, USA.
⁸ Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
⁹ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
¹⁰ Center of Molecular and Cellular Oncology, Yale School of Medicine, New Haven, CT, USA.
¹¹ Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹² Brigham and Women's Hospital, Boston, MA, USA.
¹³ Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
¹⁴ College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
¹⁵ Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.

Abstract

Background and objective: 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: 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: Clear cell RCC patients (n = 976) exhibited a significant burden of PVs in VHL compared with controls (odds ratio [OR]: 39.1, p = 4.95e-05). Non-clear cell RCC patients (n = 380) carried enrichment of PVs in FH (OR: 77.9, p = 1.55e-08) and MET (OR: 1.98e11, p = 2.07e-05). In a CHEK2-focused analysis with European participants, clear cell RCC (n = 906) harbored nominal enrichment of low-penetrance CHEK2 variants-p.Ile157Thr (OR: 1.84, p = 0.049) and p.Ser428Phe (OR: 5.20, p = 0.045), while non-clear cell RCC (n = 295) exhibited nominal enrichment of CHEK2 loss of function PVs (OR: 3.51, p = 0.033). Patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, p < 0.0001), and more than half had secondary somatic events affecting the same gene (n = 10/15, 66.7%). Conversely, CHEK2 PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, p = 0.99), and only 30.4% carried somatic events in CHEK2 (n = 7/23). Finally, pathogenic germline cryptic splice variants were identified in SDHA and TSC1, and pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL.

Conclusions and clinical implications: 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 CHEK2 due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants.

Patient summary: 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 CHEK2. We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer.

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