Cancer Genetics

Cancer arises through the stepwise acquisition of genetic changes that confer properties such as sustained proliferation, evasion of apoptosis and replicative immortality. These changes may be inherited as germline mutations or acquired during life in somatic cells. Key driver alterations fall into two broad classes: activating changes in proto-oncogenes and inactivating alterations in tumour suppressor genes. Proto-oncogenes become oncogenes when single‐base substitutions, small insertions or amplifications increase or misdirect their activity. Tumour suppressors are frequently disabled by truncating mutations, deletions or epigenetic silencing, eliminating the brakes on cell-cycle progression and DNA repair. Chromosomal instability, manifest as whole-chromosome gains or losses, arm-level copy number changes and structural rearrangements (deletions, inversions, translocations), further alters gene dosage and can create fusion genes that drive malignancy. Many sporadic cancers display a “mutator” phenotype—either because of environmental mutagens (tobacco, ultraviolet light) or defective DNA repair—leading to high burdens of point mutations. By contrast, tumours arising in the context of inherited cancer syndromes often carry far fewer somatic changes but harbour a predisposing germline lesion. Epigenetic mechanisms (DNA methylation, histone modification and altered microRNA expression) cooperate with genetic mutations to reshape gene expression programmes. Cancer thus represents a complex interplay between inherited risk, spontaneous mutagenesis, chromosomal alterations and epigenetic dysregulation, all of which converge on core pathways governing cell-cycle control, survival, genome stability and cellular interactions with the microenvironment.

Research from Nature Portfolio

A large-scale analysis of early-stage lung cancers has identified loss of the FAT1 gene—a component of Hippo signalling—as a frequent event driving two modes of chromosomal instability. Functional studies revealed that FAT1 deficiency impairs homologous recombination, heightening replication stress and generating structural rearrangements, while also promoting whole-genome doubling via dysregulated YAP1 activity. Co-depletion of YAP1 partially rescued the numerical instability but left repair defects intact, underscoring distinct downstream mechanisms by which FAT1 loss fosters tumour heterogeneity and poor prognosis.

Foundational work has shown that overactive transcription itself can be a source of oncogene-induced replication stress. Elevated expression of the general transcription factor TBP, whether downstream of RAS activation or by overexpression, increases global RNA synthesis, leading to the accumulation of RNA–DNA hybrids (R-loops), slowing replication forks and causing DNA damage. This mechanistic link between hyperactivated transcription and genomic instability provides a unifying explanation for how diverse oncogenes converge on replication stress to drive cancer evolution.

Cancer Genetics publication trend

The graph below shows the total number of articles in cancer genetics across all publications each year (not limited to Nature Index journals).

Technical terms

Oncogene: A gene whose aberrant activation—by mutation or overexpression—drives uncontrolled proliferation and tumour development.

Tumour suppressor gene: A gene that normally restrains cell growth or maintains genome integrity and whose loss accelerates cancer progression.

Chromosomal instability (CIN): The propensity of tumour cells to acquire chromosome-level alterations, including gains, losses and rearrangements.

Replication stress: Impediments to normal DNA replication that cause fork slowing or stalling, leading to DNA damage and mutagenesis.

Breakage-fusion-bridge (BFB) cycle: A mechanism of chromosomal rearrangement initiated by telomere loss or double-strand breaks, resulting in repeated fusion, breakage and missegregation.

Nuclear factor YAP1: A transcriptional co-activator regulated by Hippo signalling; its dysregulation promotes cell proliferation and genome doubling in cancer.

R-loop: A three-stranded nucleic acid structure comprising an RNA–DNA hybrid and displaced single-stranded DNA, which can induce replication stress if not resolved.

References

1. TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling. Nature Cell Biology (2024).
2. Increased global transcription activity as a mechanism of replication stress in cancer. Nature Communications (2016).
3. Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication. Cell (2023).
4. Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway. Cells (2020).
5. p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways. eLife (2018).
6. Genomic instability — an evolving hallmark of cancer. Nature Reviews Molecular Cell Biology (2010).
7. Genetics of Cancer: Past, Present and Future.