Role of inherited DNA repair deficiencies in cancer susceptibility and evolution

Abstract

Multiple DNA surveillance and repair mechanisms act on the human genome, maintaining high replication fidelity and genome stability. Deficiencies in these processes result in an accumulation of post-zygotic mutations with characteristic signatures. This genomic instability is associated with the heritability of multiple cancer syndromes. I explored the role of inherited DNA repair deficiencies in cancer predisposition, progression and evolution.

Using whole genome sequencing from family trios and a carefully curated variant calling pipeline, my results support the hypothesis that inherited DNA repair deficiencies impact germline mutational processes. Offspring from parents with germline DNA repair deficiencies have significantly increased burdens of pre-zygotic de novo mutations (DNMs) with characteristic spectra. However, phenotypic consequences of these DNMs are rare, making them unlikely to cause non-cancer diseases or developmental disorders.

Next, I investigated the recessive inheritance of variants within the base excision repair (BER) genes MUTYH and MBD4, which are associated with colorectal cancer, among other cancer types. The impact of heterozygous variants in BER pathway components is widely debated due to mixed evidence. My analyses utilising germline and somatic data from large publicly available datasets suggest that germline heterozygous variants in MUTYH do not confer significantly increased risk. Heterozygous MBD4 variants are extremely rare but may be linked to cancer susceptibility.

Finally, I identified inherited DNA repair deficiencies in ∼20% of a high grade serous ovarian carcinoma cohort. The mutational profiles of tumours indicate that inherited DNA repair deficiencies are associated with a specific signature and evolutionary trajectory of chromosomal instability. However, there may be alternative routes to chromosomal instability in tumours with proficient DNA repair.

In summary, my work demonstrates how integration of the germline and somatic mutational landscapes increases our understanding of how inherited DNA repair deficiencies impact cancer risk and evolution.