Tag Archive for: Lynch syndrome

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IGNITE-TX Study Aims to Identify Individuals for Genetic Testing for Familial Cancer

By Alexa Kanbergs, MD-ScM, MS

What is IGNITE-TX?

Have you been diagnosed with Lynch Syndrome or a BRCA1 or BRCA2 genetic mutation? Do you have family members who have not yet undergone genetic testing? If yes, then this study may be for you! The IGNITE-TX study explores ways to increase genetic testing for family members of those diagnosed with Lynch Syndrome or a BRCA1 or BRCA2 genetic mutation. This is also known as cascade genetic testing.

What the Study Involves

Individuals eligible for the study will be granted access to the IGNITE-TX website. The website contains information about their genetic mutation and how to share information with family members. Participants and their family members will be placed at random into four groups:

  • Group 1: Standard of care, which is receiving a letter with information on their specific hereditary cancer syndrome that they can share with their relatives
  • Group 2: Free genetic counseling and testing
  • Group 3: The IGNITE-TX intervention, which gives family members access to the website and education modules as well as access to a study navigator
  • Group 4: The IGNITE-TX intervention and free genetic counseling and testing.

All participants (including family members enrolled in the study) will be asked to complete a baseline survey and then follow-up surveys at 6 and 12 months. Participants will receive a $10 gift card after completion of each survey.

Why Should I Enroll? 

There are good reasons to join the IGNITE-TX Study. First, you get to help others. By joining, you can help test your family members, and it also helps us learn better ways to conduct genetic testing for people whose family has a history of cancer. Additionally, everyone who takes part in the study will be compensated for their time.

How Do I Know if I am Eligible to Enroll?

You are eligible to participate in this trial if:

  • You are 18 years of age or older
  • You or your family member has a positive genetic test result  for the BRCA1/BRCA2 mutation or Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM mutation)
  • You have an email address and/or a U.S. cell phone number
  • You speak English or Spanish

You are not eligible to participate if:

  • You do not have any relatives
  • You do not have one of the genetic conditions listed above or only have been told you have a variant of uncertain significance

Study Locations

We are targeting enrolling patients throughout the U.S.

Study Contact Information

J. Alejandro Rauh-Hain, PI

Heidy Bosch Study Coordinator

Study specific contact information: Ignitiestudy@mdanderson.org, Phone: 713 792 9155

 

Clinicaltrials.gov identifier:

NCT05677048 (https://clinicaltrials.gov/show/NCT05677048)

 

Alexa Kanbergs, MD-ScM, MS, is a Gynecologic Oncology Fellow, MD Anderson Cancer Center.

Photo credit: Rajiv Perera on Unsplash

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The Link Between Diabetes and Colorectal Cancer: Exploring the Evidence

As colorectal cancer (CRC) rates rise globally, especially in the early-onset population, identifying high-level risk factors for developing this disease becomes ever more critical. The link between diabetes and the incidence of colon and rectal cancers was discovered in 1998 and has been well-established since then, as many trials have uncovered the strength of the association between these two diagnoses. 

In 2013, a meta-analysis of 26 observational studies among more than 200,000 patients assessed the relationship between CRC and all-cause mortality (death due to any cause), cancer-specific mortality, and disease-free survival. Interestingly, diabetes was found associated with poorer outcomes for all three categories. A key finding from this study: individuals who have diabetes and CRC have a 17% increased risk of death due to any cause.

A 2017 article on the epidemiology of the association between diabetes and CRC delved into the potential molecular mechanisms of this association and the therapeutic implications of treating both diseases, and found that: 

  • Diabetes mellitus and CRC have many overlapping risk factors
  • Hyperinsulinemia, hyperglycemia, and hyperlipidemia may all play a role in the development of these dual diagnoses
  • Environmental and genetic risk factors may also play a role
  • Promising therapies for treating a dual diagnosis are statins, ACE inhibitors, anti-fibrotic agents, among others

A study among 2023 individuals evaluated the association between type 2 diabetes risk, cholesterol levels, triglyceride levels, and CRC. Additionally, the study assessed the association between Lynch syndrome—which results from a genetic mutation that can lead to CRC—and these other variables, and found that:

  • Individuals with Lynch syndrome, type 2 diabetes, and elevated cholesterol levels had an increased risk of CRC
  • High triglyceride levels in those with Lynch syndrome did not increase CRC risk 
  • Hyperinsulinemia and hyperglycemia in diabetic patients may increase the risk of CRC

A more recent study looked at the clinical and therapeutic implications of diabetes treatment and CRC risk. They found that while not always the case, these drugs often reduced the risk of dual diagnosis. Newer therapies, such as anticancer drugs that target IGF-1R and RAGE receptors (receptors for advanced glycation end products), may also help prevent and treat diabetes-induced CRC. 

It will be essential for future research to continue to explore the mechanisms behind these two diseases and to collaborate to create effective treatments for individuals experiencing dual diagnoses.

 

Emma Edwards is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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In Conversation With Dr. Alessandro Mannucci: Understanding the Relation Between Lynch Syndrome and the Oral and Fecal Microbiota

Image Credit: CDC on Unsplash

The Colon Cancer Foundation (CCF) spoke with Alessandro Mannucci, MD, who received the 2022 Colon Cancer Foundation and CGA Colorectal Cancer Research Scholar Award to present his work at the 2022 CGA-IGC Annual Meeting in Nashville, TN, November 11-13. Dr. Mannucci, a medical resident in gastroenterology and gastrointestinal endoscopy at the San Raffael Hospital, Milan, Italy, will be presenting his work titled ‘Lynch Syndrome is Associated with Fecal and Salivary Dysbiosis’.

CCF: What is the importance of the gut and the microbial flora in the human body, and how do they influence our well-being?

Dr. Mannucci: Broadly speaking, the microbiota is made up of many different cell types, including bacteria, viruses, fungi, and other kinds of microorganisms. However, our study specifically focused on bacteria because it is known that we have way more bacteria in our body than human cells. That alone indicates the significant impact of the microbiome on different phases of our life—from childhood to adulthood. 

The disruption of a healthy microbiome equilibrium causes the components of the microbiome to converge toward a proinflammatory environment in several ways. Certain species increase the risk of colorectal cancer [CRC]. Organisms that increase in numbers in the presence of CRC are generally proinflammatory. This understanding has come simultaneously with the realization that inflammation is one of the new pillars of cancer. The inflammatory environment is a disruption that is particularly important when studying the colon because the colon is the first organ in direct contact with the microbiome. 

CCF: Can you tell us the importance of this fact in your research? 

Dr. Mannucci: In our study, we had a suspect: the microbiome. While the microbiome is known to play a role in turning a normal cell cancerous, this association had not been investigated in the context of the hereditary Lynch syndrome [LS]. Mutations in one of five genes can lead to LS. 

There is a spectrum of manifestations of LS, the most important of which is CRC, although developing the cancer is determined by penetrance. We were interested in knowing if the microbiome has a role in this process.We wanted to know if the microbiome in individuals with LS who had not yet developed cancer, differed from those without LS. While it may be difficult to explain a cause-and-effect relationship, it is important to understand why a difference exists. Germline pathogenic variants may influence the formation, conformation, and diversity of the microbiome, or vice versa. Interestingly, we found that the fecal microbiota was significantly different among those with LS, but we need more data.

CCF: What is the relevance of microorganisms in the oral cavity? 

Dr. Mannucci: In individuals with LS, the cells within their mouth are also mutated. So we decided to test the differ

 Alessandro Mannucci, MD

ence between the fecal and oral microbiota among those with and without LS and found that not only is the fecal microbiota different, which you would expect because LS is associated with an increased risk of CRC, but we also observed a proinflammatory change in the oral microbiota. We now know that the oral microbiota of patients with LS differs from that of healthy individuals, which raises the question that pathogenic variants inside the mouth may interact with microbiota species that cause a proinflammatory shift. 

Another hypothesis is that individuals with this particular hereditary predisposition to CRC may also have a predisposition to orthodontic diseases. While we currently have limited understanding of this association and are testing the hypothesis, our discovery of the unexpected difference of a proinflammatory environment led us to suppose that maybe something else was at play.

What is interesting when we talk about scientific studies is not only what you are interested in, but also what you compare it to. In our case, we compared LS patients without cancer diagnosis to unrelated, healthy patients. So we did not have within-family control, which other investigators might want to look at–within the family or individuals with LS in different age groups.

CCF: How long will the subjects in your study be followed?

Dr. Mannucci: While we usually follow patients throughout their lives, five to ten years of follow-up will give us more insight. The idea is that if there is a proinflammatory environment within that patient, it could trigger cancer at an earlier age. To test that hypothesis, we are collecting samples of relatively young individuals, and we want to follow them and see if they develop cancer. The mean age of patients with LS was 48 years plus or minus 16 years.

CCF: Does diet influence microbial flora and the balance of pro- versus anti-inflammatory microbial flora in the oral cavity and the gut?

Dr. Mannucci: You raise a very, very interesting point! The microbiota is adaptable, and it can change very rapidly. There is some robustness to it, meaning you shape the health of your microbiome during your youth and by the time you reach adolescence or young adulthood, your microbiota is pretty much set. However, it can change based on your diet. 

One of our study limitations is that we could not control for diet. We could control other factors that can influence the changes within the microbiota itself, such as age, sex, smoking, the presence of cancer, or chemotherapy treatment—factors that can modify the shape, overall biodiversity, and the general composition of the microbiota.

However, we could not control the overall dietary composition. In the future, we may control our patients’ diet and place them either on a Western diet as opposed to a Mediterranean diet or a modern diet. 

Assuming that individuals with a higher risk of CRC follow an anti-inflammatory diet, you would expect to see an anti-inflammatory microbiota. We found the opposite; we found a proinflammatory change within the microbiota. While we are planning to control for participant diets in future studies, an alternative approach would be to include individuals with different genetic backgrounds and eating similar diets to investigate the differences in their microbiota. 

But remember, this is currently a hypothesis. What we know now is that these genetic predispositions are associated with a difference in the microbiota composition, and that difference itself is a proinflammatory environment. We don’t know the cause-effect relationship or how that can be altered, yet.

CCF: What would be a key takeaway from your study findings?

Dr. Mannucci: A key takeaway is that we’re developing a tool to better understand who does or does not get cancer. Hopefully, it will become a tool or a target to reduce the risk of cancer. I completely agree that diet can be a big influence. So maybe in the near future, we will be able to tell our patients that if they stop smoking, regularly exercise, reduce the intake of fatty foods, and if they have a specific kind of diet, they can reduce their risk of CRC. The microbiota has the potential to become an instrument for reducing the risk of cancer, but we are not there yet.

Thank you to Sahar Alam, CCF’s Colorectal Cancer Prevention Intern, for her assistance with this post.

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