Somatic evolution of cancer genes on the sex chromosomes

Cancer progression arises through the somatic evolution of oncogenes (OGs) and tumour-suppressor genes (TSGs). According to Knudson’s two-hit hypothesis, both alleles of a TSG must typically be inactivated for tumorigenesis to proceed, whereas a single activating mutation can drive an OG. However, this diploid framework overlooks the distinct evolutionary dynamics of sex chromosomes. In males, the hemizygous (functionally haploid) state of the X chromosome implies that only a single mutational “hit” is needed to disable an X-linked TSG, potentially accelerating its contribution to cancer development. Here, we integrate somatic population genetics models with whole-genome mutation data to investigate how ploidy and dominance shape somatic evolution. We show that X-linked TSGs in male tumours evolve significantly faster than autosomal TSGs, particularly in highly proliferative tissues, whereas in low-proliferation tumours autosomal OGs accumulate mutations more rapidly than X-linked OGs. We further demonstrate that fixation times of advantageous mutations differ systematically between OGs and TSGs, converging only for male X-linked genes, as predicted from mathematical models. Our findings reveal that haploidy of sex chromosomes fundamentally alters the dynamics predicted by the two-hit hypothesis, providing the first systematic evidence that chromosomal context biases cancer gene evolution. Incorporating these principles into cancer biology offers a more accurate framework for understanding sex differences in tumorigenesis and highlights new avenues for therapeutic strategies targeting genomic regions with accelerated mutational dynamics.