Genomic instability: mismatch repair, BRCA and xeroderma pigmentosum !

Mechanism

When DNA repair fails, mutations pile up much faster. That is why defects in repair genes cause hereditary cancers.

Updated 2026-11-01

What it is

Genomic instability is an enabling characteristic of cancer: defective DNA repair raises the mutation rate so cells acquire the hallmarks faster. Each repair pathway has its syndrome: mismatch repair (Lynch syndrome), nucleotide excision repair (xeroderma pigmentosum), homologous recombination (BRCA1/2, Fanconi anaemia, Bloom syndrome) and damage sensing (ataxia-telangiectasia). Most are inherited; the repair genes themselves behave like tumour suppressors.

Step by step

A repair gene is inactivated: one hit inherited, the second acquired, or both silenced by methylation.
Errors that would normally be corrected (mispairs, UV dimers, double-strand breaks) remain in the DNA.
The mutation rate rises sharply in that cell and its descendants.
Mutations hit oncogenes and tumour suppressors faster than in normal cells.
Cancer appears earlier and often in several organs; the tumour carries a characteristic mutational pattern.

DNA repair defects and their cancers

Pathway	Genes	Syndrome	Cancers
Mismatch repair	MLH1, MSH2, MSH6, PMS2	Lynch syndrome (autosomal dominant)	Colorectal, endometrial, ovarian, gastric, urinary tract
Nucleotide excision repair	XPA, XPC and others	Xeroderma pigmentosum (autosomal recessive)	Basal cell, squamous cell carcinoma and melanoma of the skin
Homologous recombination	BRCA1, BRCA2	Hereditary breast and ovarian cancer (autosomal dominant)	Breast, ovary, prostate, pancreas
Interstrand crosslink repair	FANC genes	Fanconi anaemia (mostly autosomal recessive)	Acute myeloid leukaemia, head and neck squamous cancers
Helicase (recombination)	BLM	Bloom syndrome (autosomal recessive)	Many cancers at young age
Damage sensing	ATM	Ataxia-telangiectasia (autosomal recessive)	Lymphomas, leukaemias

Clinical notes

Patients with xeroderma pigmentosum must avoid sunlight strictly; skin cancers can begin in early childhood.
Mismatch repair-deficient tumours respond well to immune checkpoint inhibitors because of their many neoantigens.

In the lab

Colorectal and endometrial cancers are screened for mismatch repair loss by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, or by testing for microsatellite instability.
Germline testing confirms the syndrome and allows cascade testing of relatives.

Test yourself

Think of the answer, then tap the question to see it.

Which repair pathway is defective in Lynch syndrome?

DNA mismatch repair (MLH1, MSH2, MSH6, PMS2), which leads to microsatellite instability.

What DNA lesion goes unrepaired in xeroderma pigmentosum?

UV-induced pyrimidine (thymine) dimers, normally removed by nucleotide excision repair.

Why are PARP inhibitors effective in BRCA-mutated tumours?

The tumour already lacks homologous recombination; blocking PARP-dependent repair leaves it unable to repair DNA (synthetic lethality), while normal cells survive.

What is the usual cause of microsatellite instability in sporadic colorectal cancer?

Epigenetic silencing of MLH1 by promoter hypermethylation, often with a BRAF mutation.

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Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.

Sources: Lynch syndrome: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Xeroderma pigmentosum: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); BRCA1 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); MLH1 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).

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Representative model, for educational purposes only.