DNA Repair and Genomic Instability
Genome maintenance is a network of proofreading, damage recognition, repair, checkpoint and telomere systems. Cancer can emerge when these systems fail, but each failure leaves a different molecular footprint and requires a different kind of test.
Quick answer
DNA repair deficiency and genomic instability are related but not synonymous. A repair defect may create a characteristic mutation pattern, whereas an instability measurement records the accumulated result. Gene, assay, specimen and tumour context must stay attached to the interpretation.
How the cluster fits together
Key gene profiles
DNA repair and instability library
Move from core repair mechanisms to the genomic patterns they leave behind.
POLE and POLD1 Proofreading Mutations: Ultramutated Tumours
How exonuclease-domain mutations in POLE and POLD1 drive extremely high mutation counts, and how germline and somatic findings differ in interpretation.
3 min readMUTYH-Associated Polyposis: Recessive Base-Excision-Repair Risk
Why MUTYH-associated polyposis is inherited recessively, how biallelic base-excision-repair loss drives colorectal adenomas, and what a monoallelic result does not establish.
3 min readBase Excision Repair: Small Lesions, Large Consequences
How base excision repair corrects oxidised, alkylated and deaminated bases, its links to MUTYH and PARP, and why it is described as a synthetic-lethal partner of homologous recombination.
3 min readNucleotide Excision Repair, Xeroderma Pigmentosum and Platinum Response
How nucleotide excision repair removes bulky DNA lesions such as UV photoproducts and platinum adducts, its link to xeroderma pigmentosum, and why ERCC1 has been hard to use as a biomarker.
3 min readTranslesion Synthesis: Damage Tolerance and Mutagenesis
How specialised polymerases let replication continue past unrepaired DNA damage, why this tolerance pathway is error-prone, and how it contributes to chemotherapy resistance.
3 min readThe Fanconi Anaemia Pathway: Interstrand Crosslink Repair
How the Fanconi anaemia pathway coordinates repair of DNA interstrand crosslinks, its overlap with BRCA-linked homologous recombination, and what pathway membership does and does not imply.
3 min readRECQ Helicases: Bloom, Werner and Genome Maintenance
How the RECQ family of DNA helicases protects replication and recombination, why their loss causes distinct predisposition syndromes, and the WRN synthetic-lethal link to MSI-high cancers.
3 min readMGMT Promoter Methylation: A Glioma Treatment Biomarker
What MGMT does, why promoter methylation silences it, and how methylation status is used as a predictive and prognostic biomarker in glioblastoma alkylating-agent treatment.
3 min readMutational Signatures: Reading a Tumour's History
How the patterns of mutations across a tumour genome record past exposures and repair defects, what single-base-substitution signatures mean, and the limits of signature analysis.
3 min readAPOBEC Mutagenesis: An Internal Source of Cancer Mutations
How APOBEC3 cytidine deaminases generate clustered mutations in many cancers, why the signature is often subclonal, and its emerging link to treatment resistance.
3 min readTERT Promoter Mutations: Switching Telomerase Back On
How recurrent non-coding mutations in the TERT promoter reactivate telomerase, which cancers carry them, and how they relate to alternative lengthening of telomeres.
3 min readAlternative Lengthening of Telomeres: Telomerase-Independent Immortality
How some cancers maintain telomeres without telomerase using a recombination-based mechanism, the link to ATRX and DAXX loss, and which tumour types rely on it.
3 min readChromothripsis: One Catastrophe, Many Rearrangements
How a single catastrophic shattering-and-reassembly event rearranges one or a few chromosomes, how it is recognised in sequencing data, and why it matters for cancer evolution.
3 min readWhole-Genome Doubling: A Macro-Evolutionary Step in Cancer
How a one-off doubling of the entire chromosome set buffers further mutations, its association with TP53 loss and poorer prognosis, and how it is inferred from sequencing.
3 min readHRD Scores and Genomic Scars: What an HRD-Positive Result Means
How homologous recombination deficiency is inferred from genome-wide scarring, what the component metrics measure, and why HRD-positive is not the same as a BRCA mutation.
3 min readFrequently asked questions
Is genomic instability the same as a DNA repair mutation?
No. A repair-gene alteration is one possible cause; genomic instability is an observed pattern or state that can arise through several mechanisms.
Can an HRD scar identify the responsible gene?
Not on its own. A scar can support a history of homologous-recombination deficiency, but gene-level and clinical interpretation require additional evidence.
Why do the assay and specimen matter?
Different assays measure variants, methylation, signatures or chromosome-scale changes, and tumour purity or treatment history can affect each result.