[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Neoplasia](https://durgical.com/en/general-pathology/#a-neoplasia) › Genomic instability: mismatch repair, BRCA and xeroderma pigmentosum [General pathology](https://durgical.com/en/general-pathology/) · [Neoplasia](https://durgical.com/en/general-pathology/#a-neoplasia) # 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 ## Key points - Mismatch repair (MLH1, MSH2, MSH6, PMS2): loss gives microsatellite instability; Lynch syndrome = colorectal (often right-sided), endometrial, ovarian, gastric and urinary tract cancers. - Nucleotide excision repair: removes UV pyrimidine dimers; xeroderma pigmentosum (autosomal recessive) gives skin cancers in childhood. - Homologous recombination: BRCA1, BRCA2; Fanconi anaemia and Bloom syndrome also affect double-strand break repair. - Ataxia-telangiectasia: ATM cannot sense double-strand breaks; hypersensitivity to ionising radiation, lymphomas. - BRCA-deficient tumours are killed by PARP inhibitors (synthetic lethality). - Sporadic microsatellite instability usually comes from MLH1 promoter hypermethylation, not a germline mutation. ## 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](https://durgical.com/en/conditions/lynch-syndrome/) | MLH1, MSH2, MSH6, PMS2 | Lynch syndrome (autosomal dominant) | Colorectal, endometrial, ovarian, gastric, urinary tract | | [Nucleotide excision repair](https://durgical.com/en/conditions/xeroderma-pigmentosum/) | XPA, XPC and others | Xeroderma pigmentosum (autosomal recessive) | Basal cell, squamous cell carcinoma and melanoma of the skin | | [Homologous recombination](https://durgical.com/en/conditions/hereditary-breast-and-ovarian-cancer-syndrome/) | BRCA1, BRCA2 | Hereditary breast and ovarian cancer (autosomal dominant) | Breast, ovary, prostate, pancreas | | [Interstrand crosslink repair](https://durgical.com/en/conditions/fanconi-anaemia/) | FANC genes | Fanconi anaemia (mostly autosomal recessive) | Acute myeloid leukaemia, head and neck squamous cancers | | [Helicase (recombination)](https://durgical.com/en/conditions/bloom-syndrome/) | BLM | Bloom syndrome (autosomal recessive) | Many cancers at young age | | [Damage sensing](https://durgical.com/en/conditions/ataxia-telangiectasia/) | 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. ## Memory aid Every repair crew has its disaster: no spell-checker (mismatch) gives Lynch, no sunburn crew (excision) gives XP, no double-strand welders (BRCA) give breast and ovary. ## 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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/general-pathology/genomic-instability-mismatch-repair-brca-and-xeroderma-pigmentosum/) ## Related - [Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis](https://durgical.com/en/general-pathology/tumour-suppressor-genes-rb-tp53-apc-brca-and-the-two-hit-hypothesis/) - [Hereditary cancer syndromes: the table to know](https://durgical.com/en/general-pathology/hereditary-cancer-syndromes-the-table-to-know/) - [Radiation and cancer: ultraviolet and ionizing](https://durgical.com/en/general-pathology/radiation-and-cancer-ultraviolet-and-ionizing/) - [Multistep carcinogenesis: the adenoma–carcinoma sequence](https://durgical.com/en/general-pathology/multistep-carcinogenesis-the-adenoma-carcinoma-sequence/) - [The hallmarks of cancer](https://durgical.com/en/general-pathology/the-hallmarks-of-cancer/) - [How tumours evade the immune system](https://durgical.com/en/general-pathology/how-tumours-evade-the-immune-system/) ## Related conditions - [Lynch syndrome (hereditary non-polyposis colorectal cancer)](https://durgical.com/en/conditions/lynch-syndrome/) - [Hereditary breast and ovarian cancer syndrome (BRCA1/BRCA2)](https://durgical.com/en/conditions/hereditary-breast-and-ovarian-cancer-syndrome/) - [Xeroderma pigmentosum](https://durgical.com/en/conditions/xeroderma-pigmentosum/) - [Ataxia-telangiectasia](https://durgical.com/en/conditions/ataxia-telangiectasia/) - [Bloom syndrome](https://durgical.com/en/conditions/bloom-syndrome/) - [Fanconi anaemia](https://durgical.com/en/conditions/fanconi-anaemia/) - [Colorectal cancer](https://durgical.com/en/conditions/colorectal-cancer/) - [Endometrial cancer](https://durgical.com/en/conditions/endometrial-cancer/) - [Ovarian cancer](https://durgical.com/en/conditions/ovarian-cancer/) - [Breast cancer](https://durgical.com/en/conditions/breast-cancer/) - [Prostate cancer](https://durgical.com/en/conditions/prostate-cancer/) - [Pancreatic cancer](https://durgical.com/en/conditions/pancreatic-cancer/) - [Basal cell carcinoma](https://durgical.com/en/conditions/basal-cell-carcinoma/) - [Melanoma](https://durgical.com/en/conditions/melanoma/) ## Elsewhere in DurgiPedia - [DNA repair](https://durgical.com/en/biochemistry/topics/dna-repair/) - [Types of mutations](https://durgical.com/en/biochemistry/topics/types-of-mutations/) - [DNA replication: the replication fork](https://durgical.com/en/biochemistry/topics/dna-replication-the-replication-fork/) [← All of general pathology](https://durgical.com/en/general-pathology/) 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](https://medlineplus.gov/genetics/condition/lynch-syndrome/) (MedlinePlus, US National Library of Medicine, 2026); [Xeroderma pigmentosum: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/xeroderma-pigmentosum/) (MedlinePlus, US National Library of Medicine, 2026); [BRCA1 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/brca1/) (MedlinePlus, US National Library of Medicine, 2026); [MLH1 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/mlh1/) (MedlinePlus, US National Library of Medicine, 2026). ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/general-pathology/genomic-instability-mismatch-repair-brca-and-xeroderma-pigmentosum/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/genomic-instability-mismatch-repair-brca-and-xeroderma-pigmentosum/