Lynch Syndrome

There’s no other way to say it: Romeo Milio was a dreamboat. 

He and his wife, Marie, met when they were in high school. “He had the most beautiful eyes, my weakness,” Marie remembers. “He was funny and warm, and he had a smile that could disarm anyone. How we came to be a couple is debatable. He’d say I pursued him, but I know he was definitely after me.” Either way, they spent the next 19 years together.

Lynch Syndrome: Early Diagnosis Can Lead to Prevention of Hereditary Cancers

Wonderful Gifts, a Terrifying Surprise

In December 2008, Romeo and Marie had their first daughter, Amelina Juliet. “As soon as Romeo saw her, he was instantly in love,” Marie says. In November 2010, she discovered she was pregnant again. The couple was thrilled. But unbeknownst to them a storm was brewing that would engulf their happiness.
Romeo began to suffer a constellation of symptoms, including acne on his forehead and stomach aches. His twin sister, Julie, reminded him that it had been several years since his last colonoscopy and suggested that he ought to get one. Their mother had died of colon cancer at the age of 35, and annual colonoscopies were part of their routine. Except that Romeo had missed a few.
Marie picked him up after the procedure. As they drove from the hospital, Romeo turned to her and blurted out, “I have cancer.” His gastroenterologist had discovered a tumor. The next day, Romeo had a CT scan of his abdomen. On April 5, 2011, the Milios learned the diagnosis: stage 4 colon cancer. It looked as if the disease had already spread to nearby lymph nodes, Romeo’s kidneys, and possibly his liver. He was only 36 years old.
The gastroenterologist had another piece of news: Based on the Milio family history, she suspected that Romeo might have Lynch syndrome (LS). Also called hereditary nonpolyposis colorectal cancer (HNPCC), Lynch is one of the most common hereditary cancer syndromes. A person with the syndrome has an increased risk of developing colon or rectal cancer, which usually develop from a polyp called an adenoma. For those with LS, there is also an increased risk for cancers of the endometrium (uterus), ovary, stomach, small intestine, pancreas, and upper urinary tract.

Directly to Memorial Sloan Kettering 

The Milios turned immediately to MSK where they met medical oncologist Leonard Saltz, now Chief of the Gastrointestinal Medical Oncology Service.
At MSK, the formal diagnosis of Lynch was made, and Dr. Saltz put together a chemotherapy protocol to treat Romeo’s colon cancer. However, even before his first chemotherapy appointment, Romeo’s legs started swelling and his acne grew worse; Dr. Saltz suspected something else was going on. “These symptoms didn’t fit with colon cancer,” Dr. Saltz says. It was then that the MSK team started looking for other explanations, and in addition to his colon cancer, Romeo was diagnosed with adrenocortical cancer, a very rare cancer of the adrenal gland. “Romeo had an extremely unusual story for a Lynch patient,” Dr. Saltz says. “Colon cancer in Lynch syndrome is the most common cancer we see. Adrenal gland cancer is extremely rare.” Romeo underwent aggressive surgeries to remove the colon tumor, the tumor in his adrenal gland, and the affected lymph nodes.
Dr. Saltz, who also specializes in rare cancers, such as adrenocortical cancer, designed another chemotherapy protocol to attack this new cancer. At first, it seemed to be working. Then after about three weeks, a series of what Marie describes as medical “curve balls” began. Each complication was treated, but Romeo’s condition never improved enough for him to be able to get back on chemotherapy. He passed away on October 6, 2011, seven weeks after his second daughter, Valentina, was born.

What Is Lynch?

Lynch syndrome results from problems in the way our cells repair themselves. Each of our genes is a section of our DNA, which is comprised of four chemicals known by their first letters: A, T, C, and G. Each time our cells divide, exact copies of these genes need to be made for the new cell that is formed. However, every now and then errors occur during the copying process, and the wrong chemical letter ends up in the new gene, which can keep that gene from being able to make the protein that it was designed to make.
But nature has a way of correcting these mistakes: Some of our genes make proteins that serve as “proofreaders,” catching and fixing these “typos.” One set of genes helps to find and correct a typo known as DNA mismatch, and these proteins are known as mismatch repair proteins. In Lynch syndrome, one or more genes that make a mismatch repair protein are mutated, so the protein they make cannot function and repair DNA mismatches. Thus far, researchers have identified five genes that, if there are mutations in one or more of them, can result in Lynch. When DNA mismatches cannot be repaired, a cell ends up with a great many mutations. As the genes in a cell acquire more DNA errors, the cell may finally lose its ability to grow and divide normally, and it can eventually turn into cancer.
Lynch syndrome gene alterations are called germ line mutations, meaning they are in virtually every cell in the body and can be passed from parents to their offspring. Lynch is inherited in an autosomal dominant manner; in other words, both men and women can pass it on to their children, and it only takes one mutated copy of a gene to cause the syndrome, so each child of a Lynch patient has a 50-50 chance of inheriting Lynch syndrome.

Shining a Light into the Dark 

Like many families with the syndrome, Romeo’s family had no idea about Lynch until his diagnosis. “Even though two of our uncles died at early ages from gastrointestinal-related cancers, and our aunt — our mother’s oldest sister — battled stomach cancer for nearly ten years, we were in the dark,” says Romeo’s sister Maria.
All of his sisters — Maria, Julie, and Giovanna — have since been tested at MSK, and it turns out they also have Lynch. In addition, Romeo’s cousin, Alfio, was tested. He, too, was positive for Lynch. In fact, of Romeo’s family members who have been tested, only their mother’s sixth and youngest sibling, an aunt, did not test positive for Lynch.
Since Romeo’s death, Marie and other family members have established the Romeo Milio Lynch Syndrome Foundation (RMLSF). “We didn’t want his death to be in vain,” says Marie. “Had a similar foundation existed prior to Romeo’s illness, we might have been better informed about Lynch, and our eyes certainly would have been opened as regards [to] genetic testing, screenings, and taking a more proactive role in trying to prevent cancers in our family.”
The foundation supports the research of medical oncologist Zsofia Stadler, who holds joint appointments on the Gastrointestinal Oncology Service and MSK’s Clinical Genetics Service, and Kenneth Offit, Chief of the Clinical Genetics Service. In addition, foundation funds are directed to assisting those without insurance or those who are underinsured to obtain free Lynch genetic testing.

Lynch Treatment

For people with Lynch syndrome, MSK recommends a number of risk-reducing strategies. These include yearly colonoscopies starting between ages 20 to 25; an upper endoscopy every two to four years, beginning at age 30 to 35; an annual urinalysis (to check for blood in the urine, which can be an early sign of urinary tract cancer); and for women, screenings for endometrial cancer every one to two years. In addition, for women with Lynch syndrome mutations, MSK encourages a discussion with one’s physician about risk-reducing hysterectomy and oophorectomy (removal of the ovaries) after childbearing is complete. (Romeo’s sisters Julie and Giovanna have both had hysterectomies, performed at MSK in 2014.)
Treatment for Lynch-related colon cancer usually begins with first-line chemotherapy. Some patients respond well. If a patient does not, there are new options. Immunotherapy, which has not proven to be effective in most colon cancers, has shown effectiveness in patients with Lynch-related cancers. These tumors accumulate many mutations, and the greater the number of DNA “glitches” in a tumor cell, the more abnormal proteins are generated. The odds therefore increase that the body’s immune cells will recognize the tumor cells as foreign and target them for destruction. At MSK, there are several clinical trials of an immunotherapy drug called pembrolizumab for the treatment of Lynch syndrome-related colon and other cancers. The drug has already shown effectiveness in melanoma, non-small cell lung cancer, and several other cancers.
Dr. Stadler has a special interest in caring for patients with an inherited risk for colorectal cancer and provides counseling and genetic testing for people who may have an inherited predisposition to gastrointestinal or other cancers. “Dr. Stadler was the doctor who sat down with me, my sisters Julie and Giovanna, and our aunt both before and after our genetic testing,” says Maria. “She has been very active in our foundation and is a pioneer in Lynch syndrome research. Her work is sacred to us and is empowering those diagnosed with Lynch.”

Clinical and Research Advances

Dr. Stadler’s research focuses on how best to diagnose and manage individuals with LS. With Dr. Saltz and the support of the RMLSF, Dr. Stadler has recently identified an easy and practical way of screening a patient’s tumors for Lynch syndrome through recognition of a high-mutational burden in Lynch-associated tumors. It involves literally counting the number of mutations in a tumor. The more mutations, the more likely it is that a patient has LS.
“As of 2015, we initiated testing of all patients under the age of 70 with a diagnosis of colorectal cancer for markers of mismatch repair deficiency, the hallmark of Lynch syndrome,” says Dr. Stadler. Through expansion of this screening test to a broader population of colorectal cancer patients, she and her colleagues hope to be able to better identify patients and at-risk family members who may benefit from enhanced screening recommendations. Similar expansion of screening in endometrial cancer patients is now ongoing.
For patients who are at risk of LS, MSK offers genetic counseling and testing within the Clinical Genetics Service. Erin Salo-Mullen, a Senior Genetic Counselor, focuses on the gastrointestinal genetic syndromes and has assisted Dr. Stadler in leading both research and clinical initiatives helping to raise awareness of the importance of obtaining a family cancer history of gastrointestinal cancers. “Erin was instrumental in helping to diagnose Lynch syndrome in the Milio family and subsequently in providing counseling at a very difficult and emotionally charged time for the family,” Dr. Stadler says.
“Based on feedback from our LS patients, we also initiated an annual Lynch Syndrome Educational Workshop, which provides updates on LS screening and research both here at MSK and at other institutions,” says Dr. Stadler. “On March 24, we’ll be hosting our fifth annual workshop. In addition, we now have an LS Patient Advocacy Network, a support group for LS patients that meets quarterly to discuss specific issues that individuals and families with LS face, including coping with anxiety and fear, talking to young adults in the family who may be at risk for LS, and reproductive considerations.”
“Through the generous research support of the RMLSF, we are now working on characterizing colorectal and other tumors from patients with Lynch syndrome to try to identify unique molecular signatures that may be used as prognostic and predictive biomarkers for clinical outcome,” Dr. Stadler continues. Such markers may be extremely important in determining who may or may not respond, for example, to new immunotherapies, as well as determining in earlier stage cancer which patients should receive chemotherapy after surgery.
In families with a strong cancer history where no genetic mutation has yet been identified, Dr. Stadler is part of the recently established Robert and Kate Niehaus Center for Inherited Cancer Genomics. “The aim of this center is to use next-generation sequencing to discover new cancer-causing genetic changes in families with unexplained features, including polyposis and very early onset colorectal cancer,” explains Dr. Offit, who directs the effort. “The Milio family has been an early supporter of this research, and the identification of such novel susceptibility genes can allow predictive testing in colon cancer screening in order to prevent cancer in families.”
“The Milio family has turned the tragedy of Romeo’s diagnosis into a story of hope and inspiration,” Dr. Stadler concludes. “As I have met and worked with them over the years, I’ve watched a family who suffered the formidable loss of a loved one become empowered and determined to make a real difference in the lives of others. They inspire hope and enable us to work tirelessly to ensure that, as Marie would say, no death goes in vain.” Dr. Stadler further remarks that, unlike genetic testing in breast cancer for the BRCA genes, which has received worldwide attention, Lynch syndrome and other inherited genetic syndromes for gastrointestinal cancers remain profoundly under-recognized. She adds, “The Milio family, through their dedication and commitment, has raised awareness about the importance of recognizing Lynch syndrome and has made it possible for us to do the type of research that is paving the way toward a better understanding and treatment of this syndrome.”
Learn more about the Romeo Milio Lynch Syndrome Foundation and Lynch syndrome, including free testing available at MSK for those who are uninsured or underinsured.