What is an EPCAM mutation? Which cancers does it increase the risk of?

What is an inherited EPCAM mutation? General information for carriers

• EPCAM takes its name from "Epithelial Cell Adhesion Molecule". The EPCAM gene is located on chromosome 2. And mutations in this gene affect the nearby MSH2 gene and cause Lynch Syndrome. The MSH2 gene protein plays an important role in DNA damage repair.
• Inherited EPCAM mutation carriers have a higher risk of many cancers, but large bowel (colon and rectum) and uterine (endometrial) cancer are particular risks.
• Most EPCAM mutations associated with Lynch Syndrome are thought to affect how another gene known as MSH2 works. Other names for Lynch Syndrome are Hereditary Non-polyposis Colorectal Cancer (HNPCC) and Muir Torre Syndrome—a subtype of Lynch Syndrome in people at greater risk of developing uncommon skin tumors.
• There are screening and prevention guidelines for certain cancers in people with an EPCAM deletion.
• Inherited EPCAM mutation carriers have appropriate clinical trials available to them. In addition, people who carry an EPCAM mutation and have been diagnosed with cancer may participate in certain treatments or clinical trials.
• Children who inherit an EPCAM mutation from both their mother and father may have a very rare syndrome known as "constitutional mismatch repair deficiency", which may pose a high risk of various cancers during childhood and adolescence.

Which cancers does an inherited EPCAM mutation increase the risk of?

If a genetic test for an inherited EPCAM mutation is positive, you are advised to contact a team that can review your and your family’s cancer history and help you choose the best plan to manage your cancer risk: a multidisciplinary oncology team.

The following cancers are among the EPCAM cancer risks. Compared with another Lynch Syndrome gene, MSH2, these risks are considered similar.

Table: Cancer risks for people who carry an EPCAM mutation. Source: NCCN: Genetic / Familiar High – Risk Assessment: Colorectal Version 1.2020

People who carry an inherited EPCAM mutation may also have a higher risk of other cancers. The exact risks for the following cancer types are unknown:

• Pancreatic cancer
• Sebaceous (oil cyst) skin growths
• Breast cancer in women

Studies on how mutations in the EPCAM gene affect cancer risk are ongoing.

Risk management for people who carry an inherited EPCAM mutation

The US National Comprehensive Cancer Network (US-NCCN) provides risk management guidelines for men and women with an EPCAM mutation. You are advised to contact a multidisciplinary oncology team that can review your and your family’s cancer history and help you decide on the best risk management plan.

The NCCN risk management guidelines for people who carry an EPCAM mutation include information on the following cancers:

• Colorectal cancer
• Uterine cancer
• Ovarian cancer
• Pancreatic cancer
• Urinary tract cancer
• Brain cancer
• Stomach cancer
• Breast cancer

Colorectal cancer

• Have a colonoscopy between the ages of 20 -25 (or 2 -5 years before the earliest age of colon cancer in the family if it was diagnosed before age 25).
• Repeat colonoscopy every 1 – 2 years. Talk to your doctor about whether your screening should be annual or every two years. Men, people over 40, and people with a history of colon cancer or colon polyps may benefit most from annual screening.
• Daily aspirin may reduce the risk of colorectal cancer. The best dose and timing for aspirin are not known. Current research found that taking 600 mg of aspirin daily reduced the risk of colorectal cancer in people with Lynch Syndrome. Talk to your doctor about the benefits and risks, and the best timing and dose.

Uterine cancer

• Symptom awareness and biopsy: Uterine cancer can often be detected early based on symptoms followed by a biopsy. For this reason, experts recommend that all women be aware of uterine cancer symptoms and promptly report anything persistent to their doctor.
  • Abnormal vaginal discharge
  • Pelvic or abdominal pain
  • Abdominal bloating
  • Difficulty eating
  • Frequent feeling of bladder fullness
• Screening: In the absence of symptoms, regular uterine cancer screening using transvaginal ultrasound and / or endometrial biopsies does not appear to achieve better outcomes than symptom awareness followed by biopsy for any woman with symptoms. Nevertheless, some women undergo regular screening using transvaginal ultrasound and endometrial biopsies. Transvaginal ultrasound is not recommended for premenopausal women. Women should talk to their doctor about the benefits, risks, costs and timing of transvaginal ultrasound and endometrial biopsies to make a decision about screening.
• Surgery: Removing the uterus (hysterectomy) reduces the risk of uterine cancer in women with Lynch Syndrome. However, hysterectomy has not been shown to reduce the risk of death from uterine cancer. Women should talk to their doctor about the benefits and risks of hysterectomy after completing child-rearing. The best time for surgery may vary depending on the gene mutation and the family’s cancer history.
• Drug treatment: Oral contraceptive medications (birth control medications) may reduce the risk of uterine cancer in women with Lynch Syndrome. Women should talk to their doctor about the benefits, risks and timing of contraceptive medications.

Ovarian cancer

• Surgery: Removing the ovaries and fallopian tubes (salpingo – oophorectomy) may reduce the risk of ovarian cancer in women with Lynch Syndrome. Women should talk to their doctor about the benefits and risks of salpingo – oophorectomy after completing child-rearing. The best time for surgery varies depending on the gene mutation and the family’s cancer history.
• Symptom awareness: Experts recommend that all women know the symptoms of ovarian cancer. Women should report to their doctor any of the following symptoms that last several weeks and anything different from normal:
  • Pelvic or abdominal pain
  • Abdominal bloating
  • Difficulty eating
  • Feeling full early
  • Frequent feeling of bladder fullness
• Screening: In the absence of symptoms, regular screening is performed using transvaginal ultrasound and CA125 blood tests. However, ovarian cancer screening does not help detect ovarian cancer early. Women who are not planning surgery should talk to their doctor about the benefits, risks, costs and timing of transvaginal ultrasound and CA125.
• Drug treatment: Oral contraceptive medications (birth control medications) may reduce the risk of uterine cancer in women with Lynch Syndrome. Women should talk to their doctor about the benefits, risks and timing of contraceptive medications.

Pancreatic cancer screening in people with a family history

• People who carry an EPCAM mutation and have a first- or second-degree relative with pancreatic cancer should consider screening in their early 50s or 10 years earlier than their relative’s age at diagnosis.
• For people considering pancreatic cancer screening, NCCN recommends screening at an experienced facility and ideally under research conditions. Before undergoing screening, people should talk to their doctor about its benefits, risks, costs and limitations.
• Consider annual screening with contrast-enhanced MRI-MRCP (magnetic resonance cholangiopancreatography) and / or EUS (endoscopic ultrasound).

Bladder, kidney and ureter cancer

• Consider starting annual urinalysis between the ages of 30 – 35, particularly for men and for people with a family history of urinary tract cancer.

Brain cancer

• Consider starting physical and neurological examinations between the ages of 25 – 30.

Stomach cancer

• For people with a family history of stomach cancer and / or people of Asian ancestry:

• Consider stomach cancer screening at age 40, every 3 – 5 years, using a procedure known as EGD (esophagogastroduodenocopy – esophagogastroduodenoscopy (ÖGD)).
• If stomach screening is performed, consider H. Pylori testing and treatment.

Breast cancer

• Manage your breast cancer risk based on family history. Risk-reducing mastectomy (surgical removal of the breasts) is generally not recommended.

Screening and prevention of other cancers

The guidelines do not include information on screening and prevention of other cancers for people with an EPCAM mutation. However, clinical trials may be available.

Cancer treatment for people with an EPCAM mutation

Experts are conducting research studies to learn about the best treatments for people who carry an inherited EPCAM mutation.

Most cancers in people who carry an inherited EPCAM mutation will have “MSI – high” or “MSI – H” (microsatellite instability) as a tumor biomarker. This biomarker is also known as “MMR – D” (mismatch repair deficiency). Tumor testing for MMR – D or MSI – high may be important because these tumors are more likely to respond to the immunotherapy agents known as immune checkpoint inhibitors.

MSI – H colorectal cancer

• For people with colorectal cancer, this concerns stage 2. MSI – high cancers have a good prognosis (disease course) and may not benefit from 5 – Fluorourasil adjuvant therapy (immunotherapy used in colorectal cancer).
• Keytrude (pembrolizumab) is an immune checkpoint inhibitor used to treat metastatic or advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin and irinotecan.
• Opdivo (nivolumab) is approved as an immune checkpoint inhibitor used alone or in combination with Yervoy (ipilimumab) for metastatic cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin and irinotecan.

Immune checkpoint inhibitors to treat any MSI – H cancer

• Keytrude (pembrolizumab) was approved to treat any solid tumor testing MSI – H that has progressed after treatment and has no other treatment options.

Other medical concerns for people who carry an inherited EPCAM mutation

Some mutations in the EPCAM gene cause a subtype of Lynch syndrome sometimes called Muir – Torre syndrome. In addition to the increased risk of Lynch syndrome cancers, people with Muir – Torre syndrome have a greater risk of developing uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, particularly in sun-exposed areas of the skin. An annual skin examination by a dermatologist is recommended for all individuals who carry an inherited MSH2 mutation, whether or not someone in the family has these skin tumors.

Children who inherit an EPCAM or MSH2 mutation from both their mother and father may have a very rare syndrome known as “constitutional mismatch repair deficiency (CMMRD)”. CMMRD may pose a high risk of various cancers during childhood and adolescence. Children with CMMRD syndrome may have blood (hematological) and brain / central nervous system tumors, and colorectal and other cancer types are generally seen at an older age in patients with Lynch syndrome. Most, though not all, CMMRD patients resemble neurofibromatosis, a genetic disorder that causes tumors to form on nerve tissue, particularly showing harmless, light-brown “café au lait” spots on the skin. For a child to have CMMRD syndrome, both their mother and father must have an EPCAM or MSH2 mutation. If one partner has a known mutation, couples may want to talk to a genetic counselor about testing the other partner before having children.

To select embryos without inherited EPCAM mutations, parents have the option of using assisted reproductive technology and preimplantation genetic diagnosis.