Lynch Syndrome Awareness Day: What is Lynch Syndrome?

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 results in highly elevated risks of several cancers.

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).

It’s 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.”

March 22, 2019 is Lynch Syndrome Awareness Day, and we’re encouraging everyone to join the fight against colorectal cancer. Visit our website to learn more about Lynch Syndrome and colorectal cancer.

 

 

Further reading:

Take the pledge to fight colorectal cancer: During Colorectal Cancer Awareness Month, we’re donating $10 to Fight CRC for every person who takes the pledge.

Life with Lynch Syndrome: Read about what a Lynch Syndrome diagnosis means for Carrie Ketcham and her family

Dreaming of Universal Tumor Screening: Learn how cancer genetic counselor Heather Hampel is advocating for universal tumor screening

The History of Lynch Syndrome: Dr. C. Richard Boland and Dr. Henry T. Lynch provide a broad review of Lynch Syndrome research, starting over a hundred years ago.

 

 

References

(1) Le, D.T. et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair DeficiencyNew Engl. J. Med. 372, 2509–20.

Wetlands, Water Quality and Rapid Assays

toad

The storms of the previous day had moved eastward, leaving in their wake flooded farm fields and saturated roadside wetlands. At dusk, we loaded the Ford Escort wagon and headed south. We bumped along the maze of farm roads intent upon listening for croaks and snores in the night. At one roadside wetland, I heard my first congress of Spadefoot toads. The sound was deafening, invoking everything that a “congress of snoring toads” brings to mind. Around the corner, in a low spot of a corn field, a lone Spadefoot toad called for a mate; he was joined by a rather enthusiastic Copes Gray tree frog and several chorus frogs. The congress down the road provided a rolling bass to these more melodic anurans.

Wetlands exist in many different shapes and sizes and in many different geographies: coastal margins, mountain valleys, beaches and rocky shores, estuarine wetlands where tidal saltwater and freshwater mix, and inland wetlands. Some of them are ephemeral, some of them permanent. Wetlands serve many different functions, from providing habitat and food for plants and animals to offering protection from floods and maintaining water quality. One acre of one-foot deep wetland is estimated to hold 330,000 gallons of water. Coastal wetlands are important for reducing storm erosion by decreasing tidal surge and buffering the wind. In the US alone, this benefit has an estimated value of $23.2 billion dollars each year. Continue reading “Wetlands, Water Quality and Rapid Assays”

Synthetic Biology by the Letters

Synthetic biology has been in the news a lot lately—or maybe it only seems like it because I’m spending a lot of my time thinking about our partnership with the iGEM Foundation, which is dedicated to the advancement of synthetic biology. As the 2019 iGEM teams are forming, figuring out what their projects will be and how to fund them, it seemed fitting to share some of these stories.

A, C, T, G…S, P, Z, B?

Researchers recently developed four synthetic nucleotides that, when combined with the four natural nucleotides (A, C, T and G), make up a new eight-letter synthetic system called “hachimoji” DNA. The synthetic nucleotides—S, P, Z and B— function like natural DNA by pairing predictably and evolving. Continue reading “Synthetic Biology by the Letters”

From BTCI to Africa and Back Again: One Student’s Journey in Science Education

Today’s blog is brought to us by and alumus of Dane County Youth Apprenticeship Program, Aidan Holmes.

In this blog I have the opportunity to write about how my experiences at the BTC Institute as a high school student were instrumental in leading me to my passion for science education, my Peace Corps experience, and my current role as a biotechnology instructor for the very same institute.

I became familiar with the BTC Institute as a student at Marshall High School when our biology teacher organized a biotechnology field trip for us. I loved learning about DNA and biotechnology since 7th grade so attending a field trip like this was an incredible opportunity to engage in hands-on biotechnology. When I learned about the Youth Apprenticeship Program in Biotechnology I knew I had to apply and enrolled during my senior year of high school. Through the program I took a weekly class at the BTC Institute and I worked as a student researcher in a biochemistry lab at UW-Madison. I enrolled for classes at UW-Madison the following year and pursued an undergraduate degree in genetics and a certificate in education and educational services. Continue reading “From BTCI to Africa and Back Again: One Student’s Journey in Science Education”

Mutation Analysis Using HaloTag Fusion Proteins

In a recent reference, Kinoshita and colleagues characterized the phosphorylation dynamics of MEK1 in human cells by using the phosphate affinity electrophoresis technique, Phos-tag sodium dodecyl sulfate–polyacrylamide gel electrophoresis (Phos-tag SDS-PAGE; 1). They found that multiple variants of MEK1 with diferent phosphorylation states are constitutively present in typical human cells.

To investigate the relationships between kinase activity and drug efficacy researchers from the same laboratory group conducted phosphorylation profling of various MEK1 mutants by using Phos-tag SDS- PAGE (2).

They introduced mutations in of the MEK-1 coding gene that are associated with spontaneous melanoma, lung cancer, gastric cancer, colon cancer and ovarian cancer were introduced into Flexi HaloTag clone pFN21AE0668, which is suitable for expression of N-terminal HaloTag-fused MEK1 in mammalian cells. Continue reading “Mutation Analysis Using HaloTag Fusion Proteins”

Cardboard Couture: From Conception to Runway Debut

The five-member team at the Read(y) To Wear event.

What do fashion, paperboard product packaging and literacy have in common? Answer: The Read(y) to Wear submission from a team of Promega employees for an event put on by the Madison Reading Project. With a challenge that stated teams need to make a garment mostly of paper, the resulting creations would be displayed on a runway as part of a charitable evening for an organization dedicated to bringing books to children.

Volunteering to be part of what became a five-person team to create a wearable garment from paper was the easy part. Our first few meetings we were experimenting with ideas and techniques using paper we could access on campus: Print catalogs, discarded books and our prototype product kit boxes. It was the kit boxes with the David Goodsell imagery that inspired our ideas to create a suit of armor. The paperboard boxes protect the products we ship to customers like a suit of armor protects warriors in battle. Continue reading “Cardboard Couture: From Conception to Runway Debut”

Science Visitors Only: Watching Life Grow on a New Island

We spend a lot of time looking at history and imagining—”what was it like when…?” As a biologist, I find myself most drawn to stories about the evolution of life. Why does this plant have purplish leaves? How did this species end up in a symbiotic relationship with this other species? How did this animal get to this tiny island 20 miles off the Southern coast of Iceland?

The volcanic island of Surtsey erupting in 1963.
The newly formed island of Surtsey erupting in 1963.

That last one was too specific to be rhetorical, wasn’t it? The volcanic island of Surtsey broke the ocean surface on November 14, 1963, and continued to erupt until June 5, 1967, reaching its maximum size of 2.7 km2 (about the size of Central Park in New York City). At this size, it was large enough to be a good site for biocolonization. Only a few scientists are allowed to visit the island, ensuring that colonization of the island can occur without human interference. Continue reading “Science Visitors Only: Watching Life Grow on a New Island”

Colorectal Cancer Awareness Making March About More Than Basketball

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”

A BiT or BRET, Which is Better?

Now that Promega is expanding its offerings of options for examining live-cell protein interactions or quantitation at endogenous protein expression levels, we in Technical Services are getting the question about which option is better. The answer is, as with many assays… it depends! First let’s talk about what are the NanoBiT and NanoBRET technologies, and then we will provide some similarities and differences to help you choose the assay that best suits your individual needs. Continue reading “A BiT or BRET, Which is Better?”

Radical Eradication: A (Population) Crash Course in Genetic Engineering

Malaria is a life-threatening blood disease that plagues nearly two-thirds of the world’s population. The disease in manifested by parasites of the Plasmodium genus and transmitted to humans through the bite of female Anopheles mosquitoes, which serve as the primary disease vectors. Roughly 200 million people per year are infected with malaria, and approximately 400,000 deaths are reported annually, with children under the age of five comprising the majority of victims.

Africa disproportionately bears the global brunt of this devastating illness, with approximately 92% of all reported cases, as well as 93% of all reported deaths, originating from the continent. This can be partially attributed to the fact that the conditions for transmission are essentially ideal there: the principal vector species Anopheles gambiae are abundant in this region, and not only do they prefer to source their blood from humans over animals, but the mosquitoes also tend to have a longer lifespan, which allows the most common and deadly malaria parasite, Plasmodium falciparum, to complete its life cycle, which contributes to higher disease transmission efficacy.

Though malaria is a preventable disease, often the areas affected most lack access or resources, or are politically unstable, all factors that can contribute to the absence of consistent, functional malaria control programs. Though malaria is also a curable disease, it has long been debated whether eradication was even within the realm of possibility. There are four species of Plasmodium parasites responsible for the pathogenesis of malaria and each exhibit different forms of drug resistance and each responds differently to different medications. This alone makes the prospect of developing a single overarching vaccine for all strains of malaria an improbable achievement and the idea of eradication practically impossible.

A CRISP[E]R APPROACH

In a study recently published in Nature Biotechnology, a team of scientists were able to effectively implement a new, though indubitably controversial, type of genetic modification. The team was able to weaponize mosquitoes to take out…other mosquitoes! They were able to engineer male mosquitoes to rapidly pass down a fatal mutation through generations of their own species, effectively sterilizing all female offspring, eliminating the possibility of successful reproduction and resulting in a population crash. Continue reading “Radical Eradication: A (Population) Crash Course in Genetic Engineering”