What is CHEK2? Experts discuss gene linked to breast and prostate cancer

Keri Forsythe-Stephens was at home with her young son in Canton, Georgia, about 45 minutes north of Atlanta, when her OB-GYN’s office called and requested an in-person meeting to discuss the results of his recent genetic tests.

“I just thought, ‘I’m dead.’ It was July 2020 and they didn’t want to talk to me virtually. I just knew it was going to be bad, ”said Forsythe-Stephens, who was 37 at the time and the mother of two. She agreed to be tested at her doctor’s request after revealing that her paternal aunt was diagnosed with breast cancer at the age of 49.

Five days later, she learned that she had tested positive for CHEK2, a genetic mutation linked to breast cancer in women. As the editor of a healthcare magazine, Forsythe-Stephens considered herself knowledgeable about the cancer risks surrounding BRCA1 and BRCA2 genetic mutations, however, “CHEK2 has never been discussed,” she said.

Based on his most common and aggressive variant of CHEK2 – 1100delC – and family history, Forsythe-Stephens opted to have a prophylactic mastectomy three months later. “My obstetrician told me it wasn’t my only choice. I could alternate between breast MRI and mammograms every six months, but she told me that based on my variant and my family history, if I wanted to be there for my two children, that’s the decision I made. should take. I never hesitated. As soon as I heard that my breasts could kill me, I wanted to remove them. They felt like a time bomb.

The post-mastectomy pathology report showed HER2-positive cancer cells, which tend to be aggressive and rapidly growing. “My aunt’s cancer was also HER2-positive, but she only found out she had CHEK2 after me – she had only been tested for BRCA before.”

Today, Forsythe-Stephens credits his OB-GYN for saving his life. “I know I would have developed breast cancer. The question is whether this happened after I turned 40 and started having mammograms or sooner. “

CHEK2 serves the body as a tumor suppressor, but when mutated it can be linked to many cancers. It is considered a more moderate risk genetic mutation.

Today, most people have probably heard of BRCA1, BRCA2, and PALB2 for good reason – they confer a much higher risk of developing breast cancer. Up to 10% of breast cancers are hereditary, harmful variants of BRCA1 and BRCA2 are found in 3% to 4%; and 1% to 2% of them are linked to CHEK2, noted Beth N. Peshkin, director of genetic counseling at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

In total, there are 11 breast cancer predisposition genes, BRCA1 and BRCA2 with the highest risk.

“There are maybe five genes that are considered high risk genes (when we talk about breast cancer) and what that term means is that if you inherit these abnormal genes then your risk of breast cancer is five times or more, “said Dr. Nadine Tung, a Boston-based oncologist and professor at Harvard Medical School. “It’s BRCA1 and BRCA2, PALB2 … We have certainly known PALB2 for almost a decade now and have tested it. … Then there are a few other extremely rare genes that have their own pattern of cancers. with which they are associated.… We have known them for a long time, we test them.

Still, more moderate-risk genetic mutations that confer a lifetime risk of 20-30%, on average, have become more controversial as different studies have reported varying results, Tung said. “In terms of breast cancer, (the moderate risk genes) are ATM and CHEK2, and the rest that we’re not so sure about,” she said.

“CHEK2 is on people’s radar and it’s getting on people’s radar,” said Dr. Judy Garber, oncologist and head of the division of genetics and cancer prevention at the Dana Farber Cancer Institute in Boston.

Women with the CHEK2 mutation have a moderate risk of developing breast cancer, ranging from 23% to 48% depending on their variant and family history, according to Sara Pirzadeh-Miller, deputy director of UT Southwestern Harold C. Simmons Comprehensive Cancer Center.

During this time, men with CHEK2 have an increased risk of developing Prostate cancer.

Just days after Forsythe-Stephens found out she carried the CHEK2 mutation – which her children have a 50% chance of inheriting – her father was diagnosed with stage 3 prostate cancer and learned more late that he was also a carrier of CHEK2.

“(Some) women don’t realize that a family history of prostate cancer could have implications for them if the same genes could be involved,” Garber explained. “And then men may think familial breast cancer isn’t their problem. It’s a woman’s problem. Really, hardly any of the cancer genes predispose to a single cancer, and many of them, even the ones you associate with more gender-specific conditions like prostate cancer, breast cancer, or cancer of the breast. ovary, may have implications for the opposite sex.

Dr. Alison Barron of Texas Breast Specialists also noted, “I myself see more and more CHEK2 patients who have had random genetic testing due to distant familial cancer that is unrelated to the breast.

According to Dr. David Euhus, professor of surgery and oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland, there are more than 2,500 variants of CHEK2, of which 270 are classified as possibly or definitively causing the disease. The 1100delC variant has a 24% chance that a woman will develop breast cancer in her lifetime, before considering her family history.

Dr. Phillip Ley, a Mississippi-based surgical oncologist specializing in breast cancer, discovered he was a carrier of the 1100delC variant of CHEK2 after being diagnosed with stage 1 kidney cancer. “(My variant is present in) 0.1% to 0.2% of people of North European descent, ”explained Ley. “Think about how many people that represents. It’s 1 in 1,000. It’s pretty ubiquitous. In her family, one of her two daughters carries the gene mutation, as does her brother. Her father was diagnosed with prostate cancer at 72.

In addition to breast and prostate cancers, some experts believe that CHEK2 may be associated to varying degrees with the following cancers: kidney, colon, thyroid and skin. Suggested preventive screenings for these, such as increasing the frequency of colonoscopies every three to five years, should be discussed with healthcare professionals on a case-by-case basis.

“It is important to stress that although patients with different types of cancer may have a mutation in CHEK2, it does not necessarily mean that their cancer was caused by this mutation. This is because CHEK2 is considered a medium risk gene and may be a chance discovery, ”said Dr. Alicia Latham, assistant attending physician and medical geneticist at Memorial Sloan Kettering Cancer Center in New York City. “It is also important to remember that our knowledge of CHEK2 and its associated cancers may continue to refine over time as more people undergo genetic testing and more data is accumulated.”

Emily Przybyla, of Keller, Texas, was in her mid-30s and had never had cancer – although many close relatives had – when she learned she was a carrier of the CHEK2 mutation. “At the time, I was an employee of Texas Oncology. (After) talking to a nurse practitioner about my family history of many types of cancer, she suggested that I take the test. It’s a pretty straightforward process.

Now, at age 40, her screenings include annual diagnostic mammograms as well as monthly breast exams, annual skin checks with a dermatologist and a colonoscopy every three years. “Management and screening are easy. It’s fighting cancer that isn’t, ”said the mother of two daughters. “I would rather have a colonoscopy every three years and have my polyps removed (than have) colon cancer, or have a mammogram every year than fight breast cancer. I stay on top of my health because I want to stay a long time to watch my children grow up. “

While the guidelines for organizations to determine who should request a genetic test may differ, criteria that doctors may consider include family history of cancer and age of onset, the patient’s age at diagnosis, and the type of cancer. “My own opinion is that everyone should be informed about this and make their own decision,” Euhus said.

Euhus offers tests for all breast cancer predisposing genes to all of its breast cancer patients. Sites like Color and Invitae also offer convenient and affordable genetic testing options, with panels looking for many mutations costing around $ 100 to $ 300 or less if billed through insurance.

“If a person has not had cancer – but has a strong family history, especially loved ones – the patient, or if possible, loved ones with a history of cancer should consider genetic testing,” Peshkin said, who also stressed the importance of seeing a doctor. genetic counselor before and after the test, as variants and family history play an essential role in access to risk.