DNA Repair in Prostate Cancer Learning Zone
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Glossary
The National Cancer Institute (NCI) Dictionaries of Cancer Terms and Genetic Terms were used to compile this glossary1.
| Terms related to DNA damage response | |
|---|---|
| DNA damage response |
The cellular response to any type of damage inflicted on to DNA within a cell. The response may involve cell cycle cessation, transcriptional reprogramming, damage signalling, DNA repair or cell death (apoptosis)2,3. |
| Homologous recombination repair (HRR) pathway | An accurate DNA repair pathway which repairs DNA double strand breaks in the S/G2 phase of the cell cycle. Repair involves the use of the second intact chromosome (homologue) as a template. Genes involved include BRCA2, BRCA1, ATM, ATR, CHEK1, CHEK2, PALB2, RAD51, RPA, RAD50, MRE11, NBS1, amongst others4. |
| Mismatch repair (MMR) pathway | DNA repair pathway which repairs DNA base mismatches. Repair involves the removal of the mis-inserted DNA base, and replacement with the correct base. Genes involved include MSH2, MSH3, MSH6, MLH1, PMS2 and EXO14. |
| Single strand break repair (SSBR) pathway | DNA repair pathway which repairs a break to one of the two strands of duplex DNA. Repair involves the use of the second undamaged DNA strand as a template for repair. Genes involved include PARP1, PARG, APE1, PNKP, APTX, XRCC1, LIG3, Polβ5. |
| Non-homologous end joining (NHEJ) pathway | An error-prone DNA repair pathway which repairs DNA double strand breaks throughout the cell cycle. Repair involves the re-joining of broken DNA ends. Genes involved include Ku70, Ku80, DNA-PKcs, 53BP1, Artemis, XRCC4 and LIG44. |
| Hereditary breast and ovarian cancer syndrome (HBOC) | An inherited disorder in which affected individuals are at greater risk of developing breast, ovarian, prostate, pancreatic and skin (melanoma) cancers. It is mainly caused by inherited/germline mutations in the BRCA1 and BRCA2 genes that are involved in the homologous recombination repair (HRR) pathway1. |
| Lynch syndrome | An inherited disorder characterised by inherited/germline mutations in mismatch repair (MMR) genes and mismatch repair deficiency. Affected individuals are at greater risk of hereditary nonpolyposis colon cancer (HNPCC), colorectal cancer and certain other types of cancer1,6. |
| Mismatch repair deficiency (dMMR) | Deficiency in mismatch repair caused mainly by inactivating mutations in mismatch repair (MMR) genes1. These cells usually display high levels of mutations and the presence of microsatellite instability (MSI)1. |
| Cell cycle |
A single cell cycle (G1-S-G2-M) involves cellular growth when only 1 copy of DNA is present (G1), the duplication of DNA (S) and other cellular materials, cellular growth when 2 copies of DNA are present (G2) and cellular division (M) into two daughter cells7. |
| Terms related to gene alterations | |
|---|---|
| Germline mutation |
A mutation that is inherited from a parent and is found in all cells, including tumour cells1 |
| Somatic mutation | A mutation that arises spontaneously and is found only in tumour cells1 |
| Monoallelic mutation | Only one copy of a gene is mutated, the other copy is still normal1 |
| Biallelic mutation | Both copies of the gene are mutated (not necessarily the same mutation)1 |
| Frameshift mutation | A disruption in the three-base DNA reading frame caused by an insertion or deletion of any number of bases that is not a multiple of three. If this leads to a premature STOP codon, the protein product may be truncated (shorter in length)1. |
| Loss of heterozygosity |
Presence of one normal and one abnormal allele at a chromosome locus1. |
| Genome scarring |
A genomic scar signature associated with a cellular defect. Microsatellite instability is a genomic scar signature associated with mismatch repair (MMR) deficiency. Whole genome rearrangement is a genomic scar signature associated with loss of DNA double strand break repair through loss of homologous recombination repair (HRR) or non-homologous end joining (NHEJ)2,8. |
| Terms related to molecular testing | |
|---|---|
| Cascade testing |
Genetic counselling and testing in blood relatives of patients identified to have specific pathogenic gene alterations9. |
| ctDNA |
Circulating tumour DNA is tumour DNA that has been released into the blood stream and is typically measured from cell free DNA in the plasma10,11 |
| Germline testing | Assesses germline (inherited) alterations in genes of interest. Most often involves a whole blood test, but samples may also be retrieved from a buccal swab9. |
| Tumour testing |
Assesses tumour-associated alterations in genes of interest. Tumour tissue testing is carried out on tumour samples retrieved from the tumour (for example, tumour biopsy). Circulating tumour DNA (ctDNA) testing assesses tumour DNA that has shed into the blood stream from dying (apoptotic) tumour cells9,10. |
| VUS | A variant of uncertain significance (VUS) represents a genetic change in germline DNA for which there is insufficient information to understand its impact on cancer susceptibility9. |
| Abbreviations | |
| 53BP1 | tumour protein P53 binding protein 1 |
| APC | APC regulator of WNT signalling pathway |
| APE1 | apurinic-apyrimidinic endonuclease 1 |
| APTX | aprataxin |
| AR | androgen receptor |
| ATM | ataxia telangiectasia mutated |
| ATR | ataxia telangiectasia and Rad3 related |
| BARD1 | BRCA1 associated RING domain 1 |
| BER | base excision repair |
| BRCA1/2 | breast cancer gene 1/2 |
| BRIP1 | BRCA1 interacting protein C-terminal Helicase 1 |
| CDK12 | cyclin dependent kinase 12 |
| cfDNA | cell-free DNA |
| ctDNA | circulating tumour DNA |
| CHEK1/2 | checkpoint kinase 1/2 |
| CtIP | CTBP-Interacting Protein |
| CTNNB1 | catenin beta-1 |
| DDR | DNA damage response |
| DNA | deoxyribonucleic acid |
| DNA-PKcs | DNA-dependent protein kinase catalytic subunit |
| DNA Pol | DNA polymerase |
| DSB | DNA double strand break |
| EXO1 | exonuclease 1 |
| FA | Fanconi anaemia repair pathway |
| FAM175A | family with sequence similarity 175 member A (also known as Abraxas) |
| FANCA | Fanconi anaemia, complementation group A |
| FANCD2 | Fanconi anaemia, complementation group D2 |
| GEN1 | GEN1 Holliday junction 5' flap endonuclease |
| HBOC | hereditary breast and ovarian cancer syndrome |
| HRR | homologous recombination repair |
| KMT2C/D | lysine methyltransferase 2C/D |
| Ku70/80 | Ku autoantigen, 70kDa/80kDa (same as XRCC6 and XRCC5) |
| LIG1 | DNA ligase 1 |
| LOH | loss of heterozygosity |
| MAPK | mitogen-activated protein kinase |
| MMR | mismatch repair |
| MLH1 | MutL homolog 1 |
| MRE11 | MRE11 homolog, double strand break repair nuclease |
| MSH2/6 | MutS Homolog 2/6 |
| MSI | microsatellite instability |
| NBS1 | nibrin |
| NBN | nibrin |
| NER | nucleotide excision repair |
| NGS | next generation sequencing |
| NHEJ | non-homologous end joining |
| PALB2 | partner and localizer of BRCA2 |
| PARG | poly(ADP-ribose) glycohydrolase |
| PARP1/2 | poly (ADP-ribose) polymerase 1/2 |
| PD-1 | programmed cell death protein 1 |
| PI3K | phosphoinositide 3-kinase |
| PMS2 | PMS1 homolog 2 |
| PNKP | polynucleotide kinase 3'-phosphatase |
| Polβ | polymerase beta |
| PTEN | phosphatase and tensin homolog |
| RAD50 | RAD50 double strand break repair protein |
| RPA | replication protein A |
| RAD51 | RAD51 recombinase |
| RAD51B/C/D | RAD51 paralog B/C/D |
| RAF | rapidly accelerated fibrosarcoma |
| RAS | rat sarcoma |
| RB1 | retinoblastoma 1 |
| ROS | reactive oxygen species |
| SSB | DNA single strand break |
| SSBR | single strand break repair |
| TMPRSS2:ERG | transmembrane protease, serine 2: ETS-related gene fusion |
| TP53 | tumour protein p53 |
| VUS | variant of unknown significance |
| WNT | Wingless signalling pathway |
| XLF | XRCC4-like factor |
| XRCC4 | X-Ray repair cross complementing 4 |
References
- NCI Dictionaries - National Cancer Institute. https://www.cancer.gov/publications/dictionaries. Accessed 14 June 2020.
- O’Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell. 2015;60(4):547–60.
- Sahan AZ, Hazra TK, Das S. The Pivotal Role of DNA Repair in Infection Mediated-Inflammation and Cancer. Front Microbiol. 2018;9:663.
- Athie A, Arce-Gallego S, Gonzalez M, Morales-Barrera R, Suarez C, Casals Galobart T, et al. Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer. Curr Oncol Rep. 2019;21(5):42.
- Caldecott KW. Single-strand break repair and genetic disease. Nat Rev Genet. 2008;9(8):619–31.
- Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, et al. Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol. 2019;37(4):286–295.
- Alberts B; Johnson A; Lewis J; et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. https://www.ncbi.nlm.nih.gov/books/NBK26869/. Accessed 15 June 2020.
- Lin EI, Tseng LH, Gocke CD, Reil S, Le DT, Azad NS, et al. Mutational profiling of colorectal cancers with microsatellite instability. Oncotarget. 2015;6(39):42334–42344.
- Cheng HH, Sokolova AO, Schaeffer EM, Small EJ, Higano CS. Germline and somatic mutations in prostate cancer for the clinician. Journal of the National Comprehensive Cancer Network. 2019;17(5):515–521.
- What is circulating tumor DNA and how is it used to diagnose and manage cancer? - Genetics Home Reference - NIH. https://ghr.nlm.nih.gov/primer/testing/circulatingtumordna. Accessed 14 June 2020.
- Wyatt AW, Annala M, Aggarwal R, Beja K, Feng F, Youngren J, et al. Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer. J Natl Cancer Inst. 2017;109(12). doi:10.1093/jnci/djx118.
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