Genetic basis of inherited kidney and related tumours
type: CreativeWork
description: Renal cell carcinoma (RCC) represents the 6th most commonly diagnosed cancer in males and the 10th most commonly diagnosed cancer in females, worldwide, with incidence rates rising. It has been estimated that 3-5% of RCC is inherited. The aim of this thesis was to improve the understanding of the genetic basis of predisposition to RCC by identifying the genetic architecture of inherited RCC, potential novel genetic causes and mechanisms of tumourigenesis. Additionally, evidence-based recommendations for the molecular investigation, germline variant interpretation and clinical management of patients with syndromic and non-syndromic inherited RCC are suggested. A variety of investigative approaches were utilised for this thesis. Firstly, a service evaluation was undertaken which showed a low diagnostic yield (2-3%) for a current clinical RCC panel consisting of 6 genes (*BAP1*, *FH*, *FLCN*, *MET*, *SDHB*, *VHL*). Following this I explored whether a larger panel consisting of 121 cancer susceptibility genes (CSGs) would increase the diagnostic yield and identify novel CSG and RCC phenotype associations in participants recruited with renal cancer (N=1,336) in the 100 000 Genomes Project (100KGP) which was unselected for inherited RCC risk factors. Whole genome sequencing (WGS) analysis identified 6.4% (95%CI [5.1, 7.8]) pathogenic/likely pathogenic variants (85 SNVs/indels and 3 CNVs) in a wider range of CSGs than previously recognised and mean RCC onset was 58.6 years. 24 ‘hot’ VUSs were also identified potentially increasing the diagnostic yield to 8%. Burden test analyses demonstrated excess of *CHEK2* variants in European RCC cases compared to controls (*P*=0.0019) and a trend of association with double strand homologous (DS HR) and nonhomologous repair (DS NHR) pathways. Candidate novel RCC genes were sought by familial studies on 13 trios recruited to the 100KGP and the Human Molecular Pathology of Genetic Disease (HumGenDis) study with WGS/WES data available. Tr…
abstract: Renal cell carcinoma (RCC) represents the 6th most commonly diagnosed cancer in males and the 10th most commonly diagnosed cancer in females, worldwide, with incidence rates rising. It has been estimated that 3-5% of RCC is inherited. The aim of this thesis was to improve the understanding of the genetic basis of predisposition to RCC by identifying the genetic architecture of inherited RCC, potential novel genetic causes and mechanisms of tumourigenesis. Additionally, evidence-based recommendations for the molecular investigation, germline variant interpretation and clinical management of patients with syndromic and non-syndromic inherited RCC are suggested. A variety of investigative approaches were utilised for this thesis. Firstly, a service evaluation was undertaken which showed a low diagnostic yield (2-3%) for a current clinical RCC panel consisting of 6 genes (*BAP1*, *FH*, *FLCN*, *MET*, *SDHB*, *VHL*). Following this I explored whether a larger panel consisting of 121 cancer susceptibility genes (CSGs) would increase the diagnostic yield and identify novel CSG and RCC phenotype associations in participants recruited with renal cancer (N=1,336) in the 100 000 Genomes Project (100KGP) which was unselected for inherited RCC risk factors. Whole genome sequencing (WGS) analysis identified 6.4% (95%CI [5.1, 7.8]) pathogenic/likely pathogenic variants (85 SNVs/indels and 3 CNVs) in a wider range of CSGs than previously recognised and mean RCC onset was 58.6 years. 24 ‘hot’ VUSs were also identified potentially increasing the diagnostic yield to 8%. Burden test analyses demonstrated excess of *CHEK2* variants in European RCC cases compared to controls (*P*=0.0019) and a trend of association with double strand homologous (DS HR) and nonhomologous repair (DS NHR) pathways. Candidate novel RCC genes were sought by familial studies on 13 trios recruited to the 100KGP and the Human Molecular Pathology of Genetic Disease (HumGenDis) study with WGS/WES data available. Tr…
author: Andreou, Avgi
language: eng
keywords: genomics, germline, novel gene discovery, renal cancer, whole genome sequencing
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/56f24dc7-7936-483b-8f6b-48bd7c33bc27/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-02-01
date modified: 2026-07-22T22:24:27Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.105522