Guideline: Hereditary cancer gene guidelines expand
The National Comprehensive Cancer Network regularly updates guidelines for several types of hereditary cancer. These recommendations often change when new research is published. Recently, the NCCN expanded its guidelines to include information on hereditary prostate and gastric cancers. (Posted 1/6/25)
The National Comprehensive Cancer Network (NCCN) recently updated its guidelines for Hereditary Breast, Ovarian, Pancreatic and (HBOPP) cancers and for Hereditary Colorectal, Endometrial and Gastric (HCEG) cancers. These changes reflect new research of specific genes linked to hereditary cancers.
What is important in the updated NCCN HBOPP guidelines?
Hereditary prostate cancer was added to the former Hereditary Breast, Ovarian and Pancreatic cancer guidelines, now called Hereditary Breast, Ovarian, Prostate and Pancreatic cancer (HBOPP) guidelines.
The testing criteria for genes linked to hereditary prostate cancer, such as , , , , and , have been updated. A summary of the current NCCN guidelines for genetic testing of people diagnosed with prostate cancer can be found here.
The NCCN now recommends considering genetic testing for anyone diagnosed with prostate cancer at age 55 or younger, even if they do not meet current genetic testing criteria.
What is important in the updated NCCN HCEG guidelines?
Hereditary endometrial and gastric cancers were added to the former hereditary colon cancer guidelines, now called Hereditary Colorectal, Endometrial and Gastric cancer guidelines (HCEG).
The HCEG update reflects newly updated, lower cancer risks for inherited mutations in some genes. These current risk estimates also led to revised recommendations for screening, prevention and surgery for certain genes linked to hereditary colon, endometrial and gastric cancers.
Here we report on updates related to:
mutations and their link to hereditary diffuse gastric cancer risk
mutations and their link to hereditary gynecologic cancer risk
CHEK2 mutations and their link to hereditary colorectal cancer risk
Why do cancer risk estimates change?
Risk estimates are updated when more data is collected. Initially, cancer risk estimates for most genes were based on families involved in the original research that identified the genes. These families typically included many members with cancer. Subsequent research involving individuals with a mutation in a cancer gene—including those with a weak or no family history of cancer—often results in updated and lowered cancer risks.
Additionally, if pre-cancers or early carcinomas are reclassified because new data indicates they do not lead to cancer, excluding them alters existing cancer risk estimates. For example, researchers no longer believe that people with CDH1 mutations who have T1a ( diffuse gastric cancer) changes in their stomach necessarily progress to more advanced stomach cancer. Excluding people with these changes from risk calculations lowered estimates of CDH1 cancer risk by half.
CDH1 and Hereditary Diffuse Gastric Cancer
The CDH1 gene is linked to hereditary diffuse gastric (stomach) cancer syndrome (HDGC), also called diffuse gastric and lobular breast cancer syndrome (DGLBC). HDGC is a type of stomach cancer that spreads within the inner layer of the stomach. Lobular breast cancer starts in the breast lobules, unlike the more common ductal breast cancer. The lifetime risk of lobular breast cancer among people with a CDH1 mutation is 37-55 percent. While related breast screening guidelines for this population have not changed (see current breast screening guidelines for people with CDH1 mutations here), screening recommendations for stomach cancer have been revised.
Detecting diffuse gastric cancer through screening is challenging. However, gastric cancer is often found in the inner layers of the stomach lining at an early . Early-stage diffuse gastric cancer (T1a) is usually detected in stomachs that are removed to prevent more advanced gastric cancer. During screening, most people with a CDH1 gene mutation are found to have T1a cancer in their stomach when examined by endsocopy. Because the rate of early cancer in otherwise healthy people with CDH1 mutations is high, surgery to remove the stomach (total gastrectomy) was previously recommended to prevent progression to more advanced stomach cancer.
The slightly more advanced T1b stage is found in only two to three percent of stomachs removed to prevent CDH1-associated gastric cancer. The difference in rates leads experts to believe that many people with CDH1 mutations have very early T1a cancer that may never become life-threatening. This new perspective has altered recommendations related to the risks of total gastrectomy and its intended aim to prevent HDGC-associated advanced gastric cancer.
Revised CDH1 estimates are based on people with advanced stomach cancer (excluding those with only T1a). This revised lifetime risk is lower than previous estimates. Read more in our XRAY review here. (Please note this report uses rates from one study, while rates reported below from NCCN combine multiple studies and are therefore slightly different).
Based on the most recent research available, the overall estimated risk for any stage of hereditary diffuse gastric cancer in people with a CDH1 mutation is between:
14% to 33% for women.
21% to 42% for men.
However, the estimated lifetime risk for advanced, potentially life-threatening hereditary diffuse gastric cancer (stage 2 or higher) is much lower:
6.5% for women
10.3% for men
Some families with CDH1 mutations have many members with diffuse gastric cancer, while other families with a CDH1 gene mutation have none. People with a strong family history of stomach cancer have a higher lifetime cancer risk (up to 38 percent) than individuals from families with no family history (up to 10 percent risk). Researchers do not know at this time why these differences in cancer patterns occur in families with CDH1 mutations.
Benefits and risks of screening and surgery in people with CDH1 mutations
The guidelines recommend that people with CDH1 mutations consider risk-reducing surgery to remove their stomach (total gastrectomy). The NCCN guidelines describe the benefits and risks of screening and preventive surgery.
Total gastrectomy reduces the risk of stomach cancer to less than 1 percent. While total gastrectomy is the most effective way to reduce gastric cancer risk, it is a life-altering procedure that can significantly impact quality of life. After a gastrectomy, it is difficult to properly absorb nutrients and maintain overall health. The risk of major surgery complications from total gastrectomy is 19 percent, which may be lower or higher than the risk of advanced gastric cancer, depending on family history.
Recommendations for screening or surgery
The NCCN guidelines state that people with CDH1 mutations have the option of choosing endoscopic screening or surgery (gastrectomy) to manage their diffuse gastric cancer risk. Knowledge of a family history of diffuse gastric cancer is an important consideration when making this decision. The guidelines recommend shared decision-making with healthcare providers and patients, with adequate discussion of the person’s concerns.
For people with CDH1 mutations who choose screening, the NCCN recommends upper endoscopy with random gastric biopsy every 6 to 12 months. The guidelines note that the goal of gastric cancer screening for HDGC is not to detect cancer at its earliest stage (T1a) but to detect cancer that may become life-threatening (T1b or higher). The guidelines also acknowledge limitations in distinguishing these stages.
An important benefit of screening with upper endoscopy is that related complications are rare. However, even with fewer complications, it is not known whether screening reliably detects diffuse gastric cancer early enough to treat it successfully preventing progression to more advanced gastric cancer.
Gastrectomy is another option that may be chosen instead of screening. The NCCN recommends gastrectomy over screening when:
screening detects gastric cancer that is at least stage T1b or higher.
people have gastric cancer symptoms, such as unexplained weight loss.
screening detects signs that a more advanced cancer could be present, such as ulcers (breaks in the stomach tissue).
Five genes are associated with Lynch syndrome: , , , and EPCAM. Inherited mutations in EPCAM can turn off the damage repair capability of the MSH2 gene, resulting in Lynch syndrome.
Historically, cancer risks due to EPCAM and MSH2 mutations were estimated to be the same. However, recently updated NCCN guidelines advise that the cancer risks from EPCAM mutations, especially for gynecologic cancers (like endometrial and ovarian cancer), may be lower than MSH2-associated risk and more similar to PMS2-associated cancer risks. Despite this note, the current guidelines still report MSH2 and EPCAM risks together. The NCCN recommendations related to colorectal cancer and other Lynch syndrome-associated cancers remain the same for MSH2 and EPCAM.
Considering the range of risk estimates may be useful in making decisions related to reducing the risk of gynecologic cancer. Discussing with your doctor how your personal and family history impacts your risk may help.
Challenges in understanding EPCAM mutations
EPCAM mutations are less common than mutations in the other Lynch syndrome genes, which makes it difficult to accurately estimate cancer risks. Also, experts believe the cancer risks due to EPCAM mutations may depend on the size and location of the mutation in the EPCAM gene (and the effect on MSH2).
NCCN guidelines provide recommendations for risk-management options, such as risk-reducing surgery. While risk-reducing surgeries lower the risk of certain cancers, they cause side effects, which may be significant. For example, (surgical removal of the ovaries) can greatly reduce the risk of ovarian cancer. However, it often causes menopause-like side effects, especially when performed before natural menopause. Having an accurate estimate of your cancer risk will help you weigh the risks and benefits of risk-reducing surgery before deciding if it is right for you.
If you are a female with an inherited EPCAM mutation, the NCCN recommends considering your family history to make decisions about risk-reducing surgery and/or risk management for gynecologic cancer, due to the uncertainties of gynecologic cancer risk. Delaying risk-reducing surgery, as recommended in the guidelines for PMS2 mutations, may be appropriate.
Recommendations for managing other Lynch syndrome-related cancer risks
For females with Lynch syndrome and colorectal cancer due to MSH2, MLH1 or MSH6 mutations, the NCCN recommends considering preventive hysterectomy (removal of the uterus) at the time of colorectal cancer surgery.
Guidelines for managing cancer risk, screening and prevention for healthy people with Lynch syndrome have not changed and can be found by gene here.
CHEK2 Mutations and Colorectal Cancer Risk
The CHEK2 gene is primarily associated with an increase in breast cancer risk. For many years, research showed that CHEK2 mutations also cause a small increase in colorectal cancer risk. However, newer data shows that CHEK2 mutations do not increase colorectal cancer risk.
NCCN guidelines for CHEK2 mutations no longer recommend increased screening for colorectal cancer. Instead, the guidelines suggest colorectal cancer screening based on age, family history, a personal history of and symptoms like rectal bleeding. Family history is included as a factor because this history can increase a person’s risk, even when no mutation is present.
CHEK2 mutations are also associated with breast cancer, but are not included in the HECG guideline (current recommendations can be found here).
Knowledge about risk for specific genes continues to grow. This leads to a more accurate understanding of cancer risks for people with different inherited mutations and how to manage those risks. If you have an , sharing your family’s cancer history with your healthcare providers will better inform your risk management discussions.
Medical interventions aimed at reducing cancer risk have risks and benefits. It is critical to have up-to-date knowledge of cancer risks to maximize the benefits and minimize the risks from procedures used to screen for and prevent cancer.
What does this mean for me?
The NCCN and other professional organizations regularly update guidelines based on new research. Staying up to date on guideline recommendations can help you make more informed decisions about preventing and detecting hereditary cancer.
This project was supported by the Cooperative Agreement Number, NU58DP007909, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of FORCE and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services.
Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.
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posted 1/6/25
Questions To Ask Your Doctor
I was diagnosed with prostate cancer before age 55; should I consider genetic testing?
I have an inherited mutation in CHEK2; how often should I be screened for colorectal cancer?
I have an inherited mutation in EPCAM; what are the risks and benefits of hysterectomy and salpingo-oophorectomy?
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The NCCN regularly updates guidelines for hereditary and other cancers based on new research.
These revised guidelines are relevant for people with inherited genes that cause hereditary prostate, gynecologic and colon cancers.
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