CHEK2-Related Cancer
Checkpoint Kinase 2 (CHEK2) is a serine/threonine kinase involved in cell cycle regulation and apoptosis after DNA damage has occurred. Activation of CHEK2 as a result of DNA damage inhibits a cell from initiating mitosis.
PrintCheckpoint Kinase 2 (CHEK2) is a serine/threonine kinase involved in cell cycle regulation and apoptosis after DNA damage has occurred. Activation of CHEK2 as a result of DNA damage inhibits a cell from initiating mitosis.
Evidence to date suggests that signals from damaged DNA is transmitted to CHEK2 via ataxia telangiectasia mutated (ATM). Known substrates of CHEK2 include BRCA1, BRCA2 and p53, which have all been implicated in cellular processes responsible for the maintenance of genomic stability.
Recent studies have identified founder mutations in CHEK2 in certain ethnic groups that confer an increased cancer risk. The 3 most common founder mutations in the CHEK2 gene are c.1100delC, c.444+1G>A (also known as IVS2+1G>A), and I157T (c.470T>C). The 1100delC mutation, a protein truncating mutation located with the kinase domain, is reported to abolish the kinase activity of CHEK2. It is most commonly seen among individuals of Eastern European descent, and is less commonly seen among Southern European and non-white populations. The frequencies of the IVS2+1G>A and del5395 mutations are highest in populations of Eastern European descent as well.
Multiple studies indicate that mutations in the CHEK2 gene confer an increased risk of developing many types of cancer including breast, prostate, colon, thyroid, and kidney. Carriers with a family history of breast or prostate cancer have an even higher risk of developing these cancers than CHEK2 carriers without a family history. Mutations are more likely to be found among women with bilateral versus those with unilateral breast cancers. A female carrier of a CHEK2 mutation has 1% risk per year of developing a second breast primary cancer. The Ambry Test: CHEK2-Related Cancer detects ~92% of all described mutations in CHEK2.
Checkpoint Kinase 2 (CHEK2) is a serine/threonine kinase involved in cell cycle regulation and apoptosis after DNA damage has occurred.1 Activation of CHEK2 as a result of DNA damage inhibits a cell from initiating mitosis.2 Evidence to date suggests that signals from damaged DNA is transmitted to CHEK2 via ATM (ataxia telangiectasia mutated). Known substrates of CHEK2 include BRCA1, BRCA2 and p53, which have all been implicated in cellular processes responsible for the maintenance of genomic stability.3
To date BRCA1, BRCA2, TP53, and PALB2 have been identified as breast cancer susceptibility genes; however, they do not account for all cases of familial breast cancers.4 Recent studies have identified founder mutations in CHEK2 among certain ethnic groups that confer an increased cancer risk. The 3 most common founder mutations in the CHEK2 gene are c.1100delC, c.444+1G>A (also known as IVS2+1G>A), and I157T (c.470T>C).2,5 The 1100delC mutation, a protein truncating mutation located with the kinase domain, is reported to abolish the kinase activity of CHEK2.6 It is most commonly seen among individuals of Eastern European descent, and is less commonly seen among Southern European and non-white populations. The frequencies of the IVS2+1G>A and del5395 mutations are highest in populations of Eastern European descent as well.7
Multiple studies indicate that mutations in the CHEK2 gene confer an increased risk of developing many types of cancer including breast, prostate, colon, thyroid, and kidney.2,8 Carriers with a family history of breast or prostate cancer have an even higher risk of developing these cancers than CHEK2 carriers without a family history. Mutations are more likely to be found among women with bilateral versus those with unilateral breast cancers. A female carrier of a CHEK2 mutation has 1% risk per year of developing a second breast primary cancer.4
- Individuals found to carry a CHEK2 mutation can benefit from increased surveillance and cancer risk reduction options.4
- Diagnostic testing for BRCA1- and BRCA2-negative individuals known or suspected to have hereditary breast cancers may clarify risk and guide medical management.
- Diagnostic testing in an individual with bilateral breast cancer.4
- For relatives of patients with known CHEK2 mutations, predictive testing may be desired to determine the mutation status in asymptomatic or pre-symptomatic family members. The lifetime risk of developing breast cancer in a first-degree relative with a known CHEK2 mutation is approximately 20-25%.4
- Males with family history of prostate cancer.4
This Ambry Test is a full-gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 2-15 of the CHEK2 gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. The gross deletion for exons 9-10 is also analyzed. Specific mutation analysis for individual CHEK2 mutations known to be in the family is also available.
Mutations in the CHEK2 gene account for up to:
- 5% of patients affected with familial breast cancer9
- 8.8% of patients with bilateral breast cancer8
- 18.2% of patients with hereditary breast and colorectal cancer family history12
- 4% of patients with prostate cancer13
The Ambry Test: CHEK2-Related Cancer is capable of detecting ~92% of described mutations in CHEK2.
Blood: Collect 3-5 cc into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is not available.
| Test Code | Technique |
|---|---|
| 4980 | CHEK2-Related Cancer Gene Sequence |
| 4982 | CHEK2-Related c.1100delC Founder Mutation |
| 4984 | CHEK2-Related Sequence With Exon 9 - 10 Deletion |
| Technique | Days |
|---|---|
| CHEK2-Related Cancer Gene Sequence | 10-21 |
| CHEK2-Related c.1100delC Founder Mutation | 7-14 |
| CHEK2-Related Sequence With Exon 9 - 10 Deletion | 7-14 |
1. Ahn, J et al. The Chk2 protein kinase. DNA Repair. 2004;3: 1039–1047. [PMID: 15279791]
2. Cybulski, C. et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004; 75:1131-1135. [PMID: 15279791]
3. Bahassi, EM. et al. The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage. Oncogene. 2008; 27, 3977–3985. [PMID: 18317453]
4. Narod SA. Testing for CHEK2 in the cancer genetics clinic: ready for prime time?. Clin Genet. 2010; 78:1-7. [PMID: 20597917]
5. Bell, D. et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286:2528-2531. [PMID: 10617473]
6. Wu, X. et al. Characterization of tumor-associated Chk2 mutations. J Biol Chem. 2001;276(4): 2971-2974. [PMID: 11053450]
7. Cybulski C et al. A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. J Med Genet. 2006;43:863-866. [PMID: 17085682]
8. Kilpivaara, O. et al. Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer. 2005;113:575-580. [PMID: 15472904]
9. CHEK2 Breast Cancer Consortium. CHEK2*110delC and Susceptibility to Breast Cancer: A Collaborative Analysis Involving 10,860 Breast Cancer Cases and 9,065 Controls from 10 Studies. Am J Hum Genet. 2004;74:1175-1182. [PMID: 15122511]
10. Vahteristo, P. et al.A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002;71:432-43. [PMID: 12094328]
11. Weischer et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol. 2008;26(4): 542-8. [PMID: 18172190]
12. Meijers-Heijboer, H. et al. The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet. 2003;72:1308-1314. [PMID: 12690581]
13. Dong, X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003; 72(2): 270-80. [PMID: 12533788]