Most people have two working copies of each of the MMR genes in their cells. One copy is inherited from the mother and one from the father. A change in the gene that causes it to not work properly is called a mutation. When someone inherits an MMR gene mutation from the mother and another mutation in the same MMR gene from the father, they have constitutional mismatch repair deficiency syndrome. In other words, this person has a mutation affecting each of the 2 copies of an MMR gene.
“To the immune system, foreign pathogens look very different from normal cells. But the difference with cancer cells isn’t as clear – except in microsatellite instability -high disease.
“Patients with MSI-high colorectal cancer are more likely to have their immune systems detect the tumors are different from normal tissue,” Kopetz says.
This helps lay the groundwork for immunotherapy to be effective. “The good news is the immune cells often recognize the cancer cells as different,” Kopetz says. “The barrier is the checkpoints – or the signals – that the tumor cells put on their surface to prevent the immune cells from attacking.”
This is where immune checkpoint inhibitors come in. They block the signal from the tumor cells that prevents the T cells from doing their work.
Unfortunately, only 3% of patients with metastatic colorectal cancer have MSI-high disease.
“It’s very low,” Kopetz says. “But for the first time, there’s a subset of patients where we can say, ‘Despite having metastatic disease, we can cure you with immunotherapy.’” He says that hasn’t been possible with chemotherapy and targeted therapies.
Lynch syndrome is the most common inherited predisposition to colorectal and endometrial (uterine) cancers, yet is it under-diagnosed. Around 90-95% of people who have Lynch syndrome are not aware of their condition.
This is a major concern because many of the cancers associated with Lynch syndrome are preventable or could be detected earlier through intensive cancer surveillance. Identifying patients with Lynch syndrome also helps with testing other members of their family who may be at risk and helps ensure access to care for patients who have high risks for cancer.
“Many clinicians are surprised when they find a precancerous polyp in someone younger than age 45. Our data provide new insights into how common these lesions are. Our data also suggest that clinically important lesions occur about five years earlier in individuals with a family history of colorectal cancer, compared to those without a family history,” says Dr. Itzkowitz. “That is why it is very important to take a good family history.”
We overestimate the value of reasoning and facts. We believe in our clinical authority. We expect patients to behave rationally. But we all develop our beliefs through interactions with other people — what you believe depends on whom you trust.
“The book explains his research ingrained with his very captivating family story. Boland discovered that the key factor in his family’s history of cancer was a hereditary mutation of a gene that caused, what he named, “Lynch Syndrome.””