Until last week, National Comprehensive Cancer Network (NCCN) guidelines reported that CHEK2 pathogenic variants (or risk-increasing genetic differences) are associated with an increased risk of colon cancer, citing a 5%-10% lifetime risk. NCCN recommended that carriers of a CHEK2 pathogenic variant begin colonoscopy screening earlier than typically recommended, at age 40, and repeat this screening every 5 years. (Note: recommendations for general population screening are to begin screening at age 45, and if by colonoscopy, to repeat every 10 years if no polyps are detected.)
On August 8th, 2024, NCCN published an update to the guidelines, Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric Version 1.2024 (August 8, 2024), and for the first time in many years, earlier and more frequent screening for colon cancer is no longer recommended for carriers of a CHEK2 pathogenic variant. The NCCN revised the estimated absolute risk for colon cancer from 5%–10% to “No increased risk.” Now, unless there is a family history of colon cancer, NCCN recommends colon cancer screening per general population screening guidelines for patients who carry a CHEK2 pathogenic variant.
This is a significant change and will affect care for many patients. It is also a good reminder that, as we learn more about specific risks associated with specific genetic variants, guidance on care should and will change to reflect this new information. Providers need to stay up to date and patients should be regularly following with a genetic counselor or other knowledgeable provider to stay current with screening recommendations for their specific genetic variant as these recommendations evolve over time.
National Comprehensive Cancer Network (NCCN)
NCCN is a non-profit alliance in the United States that aims to improve the quality, effectiveness, and efficiency of cancer care. Founded in 1995, it brings together a network of experts from leading cancer centers to establish and promote evidence-based guidelines for cancer treatment. NCCN also publishes guidelines on recommendations for care and screening for patients at an increased risk for cancer due to inherited genetic variants. These guidelines help healthcare providers make informed decisions about the best practices for diagnosing, treating, and managing various types of cancer as well as guide care for patients with an increased genetic risk for cancer.
NCCN guidelines are typically updated on a yearly basis. However, they can be revised more frequently if new evidence or significant changes in clinical practice arise that necessitate an update. The NCCN continually reviews and updates its guidelines to reflect the latest research, advancements in cancer treatment, and emerging clinical data.
CHEK2
The CHEK2 gene, also known as Checkpoint Kinase 2, is a DNA damage repair gene that was first described in 1998. In 2001, questions were raised about the possible association of a ‘breast-colon cancer syndrome’ with germline (or inherited) variants in the CHEK2 gene. Many studies followed that considered a possible increased risk for colon cancer on the basis of inherited variants in CHEK2.
CHEK2 encodes a protein that has an important role in monitoring and repairing DNA damage by helping regregulate the cell cycle. Specifically, this protein is a serine/threonine kinase that signals for cell cycle arrest in response to DNA damage, allowing time for DNA repair. If the damage is too severe, CHEK2 can also promote apoptosis (programmed cell death) to prevent the propagation of damaged cells.
By controlling repair processes and preventing damaged cells from dividing, CHEK2 functions as a tumor suppressor. This role is crucial for maintaining genomic stability and preventing cancer from developing.
For this reason, inherited variants or mutations in the CHEK2 gene that impair its function have been associated with an increased risk of cancer.
CHEK2-Associated Breast Cancer Risk
While pathogenic variants in the CHEK2 gene generally confer a lower risk of cancer than variants in high-risk genes (such as BRCA1 or BRCA2), they still significantly impact cancer risk. Some specific types of variants (truncating variants) affect the risk more than others (missense variants). Individuals who were assigned female at birth with inherited CHEK2 pathogenic variants have an increased risk for breast cancer, currently estimated to be between a 15%-40% lifetime risk. Individuals assigned male at birth with CHEK2 pathogenic variants also have an increased risk for breast cancer as compared to the general population, although specific risk figures are not yet defined.
CHEK2-Associated Colon Cancer Risk
For many years it has been reported that CHEK2 pathogenic variants increase the risk for colorectal cancer, with the NCCN previously reporting an estimated lifetime risk of 5-10% compared to the general population risk of 4%. However, recent studies have reported a small to no-increased risk for colon cancer. One recent retrospective study of nearly 4,000 patients with pathogenic variants in CHEK2 found no increased risk for colorectal cancer. The NCCN has now revised its CHEK2 guidelines and reports no increased risk of colorectal cancer and recommends general population colorectal cancer screening in the absence of a family history of colorectal cancer.
CHEK2 and Other Cancer Risk
There is some preliminary evidence suggesting that truncating variants in the CHEK2 gene may be associated with an increased risk for prostate cancer in patients assigned male at birth. For this reason, NCCN guidelines suggest consideration of annual prostate cancer screening with prostate specific antigen (PSA) testing beginning at age 40, in the context of shared decision-making with a healthcare provider.
Some studies have suggested that some CHEK2 variants may be associated with an increased risk of thyroid, pancreatic, kidney, and stomach cancers. However, such evidence is limited and more research is needed to make a determination regarding these associations before any recommendations for screening for these cancers can be recommended. There is insufficient evidence to suggest that CHEK2 pathogenic variants are associated with an increased risk for ovarian cancer at this time.
Current Guidelines for Cancer Screening CHEK2
There are currently two main guidelines referenced for cancer screening of patients who carry pathogenic variants in the CHEK2 gene:
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric Version 1.2024 — August 8, 2024
- Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
These guidelines are more or less consistent with one another and are as follows:
Breast Cancer:
Individuals Assigned Female at Birth Who Carry Truncating Variants
- Annual mammogram to begin at age 40 and consider breast MRI with and without contrast starting at age 30–35 years
Individuals Assigned Female at Birth Who Carry Missense Variants
- General population breast cancer screening with increased screening tailored to the family history
Individuals Assigned Male at Birth Who Carry Truncating Variants
- Advise patients on breast self-examination and symptom awareness
Prostate Cancer
Individuals Assigned Male at Birth Who Carry Truncating Variants
- Discuss PSA prostate cancer screening through shared decision-making with a healthcare provider, particularly when there is family history of prostate cancer; increased-risk prostate cancer screening may include annual PSA testing beginning at age 40
Colon Cancer
Manage based on family history. If no family history of colorectal cancer, general population screening is recommended.
Per the NCCN, as long as there is no personal or family history of colon cancer or polyps, general population screening for colon cancer from ages 45-75 includes one of the following:
- Colonoscopy every 10 years -OR-
- Stool- Guaiac-based testing or Fecal immunochemical test (FIT) every year -OR-
- Multi-targeted stool DNA (mt-sDNA)-based testing every 3 years -OR-
- Flexible sigmoidoscopy every 5 years -OR-
- CT colonography every 5 years
Here is an excellent review for patients about different colon cancer screening options.
Conclusion
NCCN guidelines have recently updated their recommendations for patients who carry CHEK2 pathogenic variants, moving away from any increased screening for colon cancer. This is an important reminder that, as new information becomes available through research, our understanding of the risks associated with different genetic variants changes, and the recommendations for care also change.
If you carry a genetic variant associated with cancer risk, you are encouraged to check back with a genetic counselor every 3-5 years to learn if there is any updated information on your variant that may change your care.
References:
Husain, S., K. J. Kohn, P. S. Gonzalez, J. J. B. Choi, and A. H. K. Mincheva. “Checkpoint kinase 2 (CHEK2) gene and its mutations.” Journal of Medical Genetics, vol. 35, no. 9, 1998, pp. 700-704.
Lipton L, Thomas HJ, Eeles RA, Houlston RS, Longmuir M, Davison R, Hodgson SV, Murday VA, Norbury CG, Taylor C, Tomlinson IP. Apparent Mendelian inheritance of breast and colorectal cancer: chance, genetic heterogeneity or a new gene? Fam Cancer. 2001;1(3-4):189-95. doi: 10.1023/a:1021101014264. PMID: 14574178.
Bychkovsky BL, Agaoglu NB, Horton C, Zhou J, Yussuf A, Hemyari P, Richardson ME, Young C, LaDuca H, McGuinness DL, Scheib R, Garber JE, Rana HQ. Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care-Checking CHEK2. JAMA Oncol. 2022 Nov 1;8(11):1598-1606. doi: 10.1001/jamaoncol.2022.4071. PMID: 36136322; PMCID: PMC9501803.