Similar to the evolution in any species, the ~1014 cells in the human body are “subject to the forces of mutation and selection.” This process of somatic evolution begins in the zygote (fertilized egg). And it only comes to rest at death, whereas cells are constantly exposed to mutagenic stresses — introducing 1 to 10 mutations per cell division…!! These mutagenic forces lead to a gradual accumulation of point mutations throughout one’s life, which can be observed in a range of healthy tissues, as well as cancers. Although these mutations are “predominantly selectively neutral passenger-mutations,” some are proliferatively advantageous driver mutations. Types of mutation in cancer genomes are well studied, but little is known about when these lesions arise during somatic evolution, and where the boundary should be drawn — between normal evolution and cancer progression.
Comprehensive genomic characterization of tumors has been a major goal of cancer researchers — from the time the first human genome had been (mostly) sequenced in 2001. Since then, advances in sequencing technology and analytical tools have allowed this research field to explode. In six papers in the 6 Feb 2020 issue of Nature, the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium presents the most comprehensive and ambitious meta-analysis of cancer genomes to date. Unlike previous efforts — that focused largely on protein-coding regions of the cancer genome — PCAWG analyzed whole genomes. Each article scrutinizes an important aspect of cancer genetics; together, their findings can help us understand the full genetic complexity of cancer.
Of the six papers, these GEITP pages have selected paper #5 as most closely related to the topic of gene-environment interactions. Cancer evolution is most effectively studied by sequencing multiple regions of a tumor, over time, but it can also be reconstructed from a single biopsy: this is the approach taken by these authors [see attached article]. Authors introduce the concept of ‘molecular time’ — to classify clonal and subclonal mutations. They reasoned that subclonal mutations (which are present in only a subset of a tumor’s cells) must have arisen late in the cancer’s evolution. They classified clonal mutations (which are present in all of a tumor’s cells) as “early” vs “late”, depending on whether the mutations arose before, or after, the clone underwent copy-number gains (i.e. an increase in number of copies of a gene or chromosomal region). Authors combined evolutionary data from multiple tumors — which allowed the authors to identify common mutational trajectories (e.g. APC–KRAS–TP53 progression, which describes the typical sequence in which mutations arise in colorectal cancer).
Authors found that the driver mutations — that most commonly occur in a given cancer — tend to occur earliest. Similarly, if copy-number gains are highly recurrent in a particular cancer-type, they tend to occur early (e.g. a copy-number gain in part of chromosome 5 is common in clear-cell kidney cancer, and tends to arise early in the disease’s evolution). Conversely, whole-genome duplication is a relatively late event in this cancer. Lastly, authors found that mutational signatures often change over time; these changes reflect a decreasing role for environmental exposures in cancer progression, and an increase in frequency and severity of DNA-repair defects.
By whole-genome sequencing (WGS) analysis of 2,658 cancers, authors [see attached article] reconstructed the life history and evolution of mutational processes and driver mutation sequences in 38 types of malignancies. Early oncogenesis (tumor development) is characterized by mutations in a constrained set of driver genes, and specific copy number gains (e.g. trisomy 7 in glioblastoma, isochromosome 17q in medulloblastoma). [These early changes are what researchers in the 1970s had named “tumor initiation.”] Throughout tumor evolution in 40% of samples, the mutational spectrum changes significantly: an almost 4-fold diversification of driver genes, and increased genomic instability — are features of later cancer stages. [These late changes are what researchers in the 1970s had called “tumor promotion,” also termed “tumor progression.”] Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades…!! Together, these data determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection and possible treatment. 😊.