Analyses of the Association between Y-Chromosomal Haplotypes, AZFc Copy Number Variants and Testicular Germ Cell Tumours using Large-Scale Genomic Data
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Embargo End Date
2026-09-10
ICR Authors
Authors
Choi, S
Document Type
Thesis or Dissertation
Date
2026-03-10
Date Accepted
Abstract
Testicular germ cell tumour (TGCT) is the most common malignancy in young men of European ancestry with familial studies demonstrating high heritability. Although genome-wide association studies (GWAS) have accounted for a sizeable proportion of genetic risk, more than half of TGCT heritability remains unexplained. Given the male specificity of TGCT, variants on the Y chromosome (ChrY) represent plausible contributors to disease risk.This thesis presents analyses relating to two distinct ChrY-specific genetic variations, (i) Y-DNA haplogroups (Y-Hgs), which captures lineage specific effect transmitted through paternal inheritance, and (ii) AZFc copy-number variants (AZFc-CNV), with particular focus on the long-debated gr/gr deletion. Large-scale genomic datasets (whole-genome sequencing, whole-exome sequencing, and SNP array data) of TGCT cases and controls from the UK Biobank (UKB), the Testicular Cancer Consortium (TECAC), and other international collaborators were leveraged. Using the Yleaf classifier and WGS data, which provided the highest resolution for haplogroup inference, I analysed 7,930 European-ancestry males from UKB and TECAC. No significant association was observed between major Y-haplogroups and TGCT; however, the sub-haplogroup R1a1a1 showed a reproducible moderate association (OR > 1.5), independent of the gr/gr deletion, and acted as a confounder in AZFc-CNV analyses.Optimised CNVkit-ampliconic pipelines, benchmarked across sequencing depths and validated against PCR assays, were applied to the largest TGCT case-control study of European-ancestry males to date (2,948 TGCT cases and 4,947 controls; plus 2,554 TGCT cases and 196,209 controls in the extended UKB). No significant associations were found between gr/gr deletions and TGCT, nor with other AZFc-CNVs. A phenome-wide association study (PheWAS) of 42 male-biased cancers in UKB likewise showed no association with gr/gr deletion. Only gr/gr duplication was associated with malignant neoplasms of the urinary tract (OR=4.64).This work also delivers validated computational pipelines for ChrY analysis in population-scale genomic studies. Overall, these findings indicate that Y-chromosomal variation exerts at most a modest influence on TGCT risk.
Citation
2026
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)