Oncologists, do you know your colorectal cancer patients’ MSI status?
High-frequency microsatellite instability (MSI-H) in tumors is a form of genomic instability where mismatch repair (MMR) proteins fail to properly correct errors in microsatellite regions of the genome. When a patient’s tumor tissue is determined to have MSI-H markers, it’s strongly recommended that they be further tested for Lynch syndrome, a hereditary condition that puts them and their family at a higher risk of developing colorectal and other cancers (1).
Though as many as 1 in 279 people might be carriers for the mutations associated with Lynch syndrome (2), 95% of them don’t know it (3). Furthermore, people with Lynch syndrome have an approximately 80% increased lifetime risk of developing colorectal cancer, compared to a risk of only ~4% for the general population (4, 5).
On Lynch Syndrome Awareness Day, here are three key reasons why you should test all your colorectal cancer patients’ MSI status.
Lynch Syndrome is the autosomal dominant hereditary predisposition to develop colorectal cancer and certain other cancers. This simple, one sentence definition seems woefully inadequate considering the human toll this condition has inflicted on the families that have it in their genetic pedigree.
They Called it a Curse
To one family, perhaps the family when it comes to this condition, Lynch Syndrome has meant heartache and hope; grief and joy; death and life. Their story is told by Ami McKay in her book Daughter of Family G, and it is at once both a memoir of a Lynch Syndrome previvor (someone with a Lynch Syndrome genomic mutation who has not yet developed cancer) and a poignant and honest account of the family that helped science put name to a curse.
“The doctors called it cancer. I say it’s a curse. I wish I knew what we did to deserve it.”
Anna Haab from Daughter of Family G (1)
The scientific community first met “Family G” as the meticulously created family tree, filled with the stunted branches that mark early deaths by cancer. The pedigree was first published in 1913 in Archives of Internal Medicine (2). In the article, Dr. Alderd Warthin wrote: “A marked susceptibility to carcinoma exists in the case of certain family generations and family groups.” In 1925, an expanded pedigree of circles and squares was published in Dr. Warthin’s follow up study in the Journal of Cancer Research (3). But each circle and square in that pedigree denotes a person. Each line represents their dreams together for the future, and Ms. McKay wants us to know their names: Johannes and Anna, Kathrina, Elmer, Tillie, Sarah Anne (Sally); and—most importantly—Pauline. Because without Pauline there would be no story.
There are as many different
cancers as there are people with cancer. Unlike infectious diseases, which are
caused by pathogens that are foreign to our bodies (bacteria, viruses, parasites),
cancer cells arise from our body—our own cells gone rogue. Because cancer is a
dysfunction of a person’s normal cells, every cancer reflects the genetic
differences that mark us as individuals. Add to that environmental influences like
diet, tobacco use, the microbiome and even occupation, and the likelihood of
finding a “single” pharmaceutical cure for cancer becomes virtually impossible.
But, while looking for a single cure for all cancers may not be a fruitful activity, defining a best practice for understanding the genetic and protein biomarkers of individual tumors is proving worthwhile.
Lynch Syndrome is a hereditary condition caused by germline mutations that inactivate at least one of the major DNA mismatch repair (MMR) genes. Individuals with Lynch Syndrome have an elevated risk of developing several cancers, especially colorectal, uterine and endometrial. Approximately 1 in 279 individuals in the United States is Lynch-positive, but most people are unaware of their status.
Lynch Syndrome can be diagnosed following screening by microsatellite instability (MSI) analysis or immunohistochemistry (IHC) for the MMR proteins. For some patients, MMR gene sequencing is as easy as an oral “swish.” However, the genetic basis of Lynch Syndrome and its clinical relevancy are relatively recent discoveries. Long before modern sequencing methods simplified testing and diagnosis, a seamstress in Ann Arbor, Michigan correctly predicted her own Lynch Syndrome status based only on her family history. Talking with Dr. Alfred Scott Warthin in the late 19th century, she said that since so many of her family members had died of several specific cancers, she believed that she would follow the same path. Several years later, she unfortunately proved herself right.
Dr. Warthin took interest in the story and began studying the woman’s family. At the time of their conversation, five of her nine siblings had already been diagnosed with uterine, stomach or “abdominal” cancer. Warthin concluded that the family, which he dubbed “Cancer Family G,” did, in fact, have a predisposition to cancer. Warthin and other researchers continued studying the family for several decades. They found that cancers of the colon, uterus and stomach were most common, and that many members of the family were diagnosed at extraordinarily young ages.
In the 1970s, Dr. Henry T. Lynch organized a family reunion for Cancer Family G and subsequently published a report on “Cancer Family Syndrome.” By this time, 95 members of the family had developed one of the expected cancers. Dr. Lynch still didn’t have the technology to determine the molecular basis of the disease, but he noticed that it followed an autosomal dominant inheritance pattern.
In the mid-1990s, three labs simultaneously discovered microsatellite instability and its connection to colorectal cancer. It had been established in bacteria and yeast that inactivating mutations in DNA mismatch repair genes resulted in mutations in microsatellite sequences, so several labs began racing to clone the human homologs of the DNA MMR genes. Within a few months, two labs had cloned the MSH2 gene and found mutations that were present in members of Lynch-positive families who developed cancer.
Around this time, the name “Lynch Syndrome” was adopted to apply to families carrying germline mutations in a gene associated with the condition. Further research established four genes (MSH2, MLH1, MSH6, PMS2) as “Lynch Syndrome Genes,” and researchers began working on guidelines for diagnostic testing (See “The History of Lynch Syndrome” below for further reading).
Today, over two decades later, many researchers are pushing for the adoption of universal tumor screening for Lynch Syndrome. One of the widely recommended screening method is MSI analysis. MSI-H status indicates that certain sections of DNA called microsatellites have become unstable because the major mismatch repair genes that correct errors during DNA replication are not functioning properly. MSI status can influence treatment decisions, based on the 2015 discovery that MSI-H tumors respond well to immunotherapy drugs (1).
Lynch Syndrome awareness is also important knowledge for a patient’s family. Lynch-associated cancers are among the most preventable, so individuals who know they are Lynch-positive can work with their healthcare providers to develop robust strategies for prevention and surveillance. As one Lynch-positive mother said to her Lynch-positive son, “Your knowledge is power, and it’s going to keep you healthy and safe.”
In the United States, March means college basketball. “March Madness” brings us the excitement and entertainment of the NCAA college basketball championship tournament. But for a dedicated group of advocates, researchers, patients and families, it means something else entirely. March is colorectal cancer awareness month.
According to the American Cancer Society, colorectal cancer will be the third most frequently diagnosed and the second most deadly cancer in the United States in 2019 (1). Most of those who develop colorectal cancer do not have a family history or genetic connection to the disease. However, in some families, cancer occurs more often than expected. A family history of colorectal cancer can suggest a genetic factor. Continue reading “Colorectal Cancer Awareness Making March About More Than Basketball”
The 2018 Nobel Prize in Physiology and Medicine was awarded to James P. Allison of the United States and Tasuku Honjo of Japan for their work to identify pathways in the immune system that can be used to attack cancer cells (1). Although immunotherapy for cancer has been a goal for many decades, Dr. Allison and Dr. Honjo succeeded through their manipulation of “checkpoint inhibitor” pathways to target cancer cells.
Immune checkpoint inhibitor drugs have been effective in cancers such as aggressive metastatic melanoma, some lung cancers, kidney, bladder and head and neck cancers. These therapies have succeeded in pushing many aggressive cancers below detectable limits, though these cases are notably not relapse-free or necessarily “cured” (2,3).
One challenge in implementing immunotherapy in a cancer treatment regime is the need to understand the genetic makeup of the tumor. Certain tumors, with specific genetic features, are far more likely to respond to immune checkpoint therapy than others. For this reason, Microsatellite Instability (MSI) analysis has become an increasingly relevant tool in genetic and immuno-oncology research.
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