There are at least 450 genes associated with DDR [1, 2]. Some identified examples of DDR genes known to be involved in cancer are shown in the table below. Several DNA repair and DDR signalling proteins are associated with familial cancer predisposition syndromes (due to inactivating germline mutations) and with somatic mutations in sporadic cancers [1-4].
DDR deregulation may lead to cancer through various mechanisms [5-10].
- Dysregulation of one or more DDR pathways
- Increased levels of replication stress
- Increased levels of endogenous damage
- Some combination of the above, and/or sustained by the application of anticancer therapies such as radiation or chemotherapy
Table 5: Examples of DDR genes associated in cancer
DNA repair |
Gene |
Cancer-associated mutations |
---|---|---|
BER |
OGG1 |
Renal, breast and lung cancer |
XRCC1 |
Non-small cell lung cancer |
|
NER |
ERCC1 |
Lung and skin cancer, and glioma |
XP |
Xeroderma pigmentosum predisposing to skin cancer. Also increased risk of bladder and lung cancer |
|
MMR |
MSH2, MLH1 |
Lynch syndrome predisposing to colorectal cancer as well as endometrial, ovarian, stomach, hepatobiliary tract, upper urinary tract, brain and skin cancer |
HRR |
BRCA1, BRCA2 |
Increased risk of breast, ovarian, prostate, pancreatic, as well as gastrointestinal and haematological cancer, and melanoma |
FANC |
Group of proteins associated with Fanconi anaemia predisposing to squamous cell carcinomas of the head and neck and acute myeloid leukaemia (e.g. FANCA, FANCB) |
|
NHEJ |
KU70 |
Breast, colorectal and lung cancer |
KU80 |
Lung cancer |
|
Cell cycle |
ATM |
Ataxia-telangiectasia predisposing to leukaemia, breast and pancreatic cancer |
ATR |
Leukaemia, lymphoma, gastric and endometrial cancer |
|
P53 |
Li-Fraumeni syndrome |
Table includes both germline and somatically derived mutations.
BER, base excision repair; HRR, homologous recombination repair; NER, nucleotide excision repair; NHEJ, non-homologous end joining; MMR, mismatch repair.
References
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- Pearl LH, Schierz AC, Ward SE et al. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer 2015; 15: 166-180.
- Dobbelstein M, Sorensen CS. Exploiting replicative stress to treat cancer. Nat Rev Drug Discov 2015; 14: 405-423.
- Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer 2016; 16: 35-42.
- Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 2008; 26: 3785-3790.
- Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017; 355: 1152-1158.
- Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434: 917-921.
- Bryant HE, Schultz N, Thomas HD et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434: 913-917.
- Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 2012; 12: 801-817.
- Lucchesi JC. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanfgaster. Genetics 1968; 59: 37-44.