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Lynch syndrome-associated colorectal cancer, what can your microbes do for you?

Lynch syndrome (previously known as hereditary non-polyposis colorectal cancer, HNPCC) is a type of inherited cancer syndrome in which an affected individual is genetically predisposed to a number of cancers. Although primarily associated with colorectal cancer, the mutations that occur in people with Lynch syndrome are also linked with cancers such as endometrial, stomach, breast, ovarian, small bowel, pancreatic, prostate, urinary, liver, kidney and bile duct cancers … hence the change in name. Despite this long list, Lynch syndrome cancers continue to dominate the gut, perhaps reflecting the inability to detect tumours until they present with overt symptoms such as bleeding, an increasing trend for colorectal cancers in our modern society or even a unique mechanism that is most analogous with the gut.

Lynch syndrome is caused by a fault, or mutation, in the genes that normally protect us from developing cancer. These genes are called mismatch repair genes, and they detect small mutations in our cells which can lead to cancer. Faults in these mismatch repair genes can lead to some mutations in our cells going undetected, allowing cancer to develop without proper control. This means that people with Lynch syndrome are at a greater cumulative risk of developing cancer, with a lifetime risk of 70-90%, and they are also likely to develop it at a younger age (40-50 years, compared to 60-70 years amongst the general population).

So what does this mean for people with Lynch syndrome?

Ultimately, a diagnosis of Lynch syndrome means a lifetime of surveillance. For bowel cancer this means regular colonoscopies, but for other cancers the surveillance tactics are down to the discretion of the treating physician and the individual, as policy changes regularly. Now although yearly colonoscopies may not sound like a lot of fun, there is a plus side to it! A strong and growing body of data now indicate that those with Lynch syndrome are actually much less likely to die as a result of colorectal cancer compared to their non-Lynch syndrome counterparts. This likely reflects their commitment to surveillance strategies, meaning tumours are detected earlier and are therefore much easier to treat successfully.

The microbiome and Lynch syndrome

Despite a growing body of evidence implicating the microbiome in the development of colorectal cancer, there is a scarcity of data specifically related to Lynch syndrome. This is concerning as this is a well characterised cohort of people known to be at a much greater risk of cancer than the general population. As such, simple, cost-effective and non-invasive methods of reducing their risk would be of great public health significance and personal benefit.

In 2017, a group from Beijing reported alterations in Fragelis, parabacteroides distasonis and pseudomonadaceae in people with Lynch syndrome. However, this was only published as a short abstract, with little to no information regarding their methodology. This makes interpreting their results extremely difficult and any conclusions should be made with extreme caution. Furthermore they were unable to conclude if the changes detected were causative of disease or purely reflective of the genetic mutation at the core of Lynch syndrome. So this study really does not add much weight to the argument of whether the microbiome are important in the development of Lynch syndrome cancers.

There is however an ongoing trial listed at Memorial Sloan Kettering Cancer Centre in which people with Lynch syndrome are being enrolled for stool analysis. This appears to be well-designed and will hopefully pave the way for a better understanding of how the microbiome could be used to reduce the risk of colorectal cancer in people with Lynch syndrome.

Is there a role for probiotics in the prevention of colorectal cancer?

Probiotics are defined as live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. They are certainly well characterised for their ability to change the composition of the microbiome, at least transiently, and have had some success in managing a number of gastrointestinal diseases such as irritable bowel syndrome. Based on the increasing number of studies reporting altered microbiome composition in the development of colorectal cancer, their role in cancer prevention certainly deserves some investigation.

In animal models of colorectal cancer, the results are inconsistent, reflecting the way in which the disease is induced, probiotic formulations, probiotic doses, rodent husbandry conditions and analysis of disease severity. The only clear evidence coming out of these studies is that probiotic intervention must be adopted very early in disease progression, or ideally before carcinogenic events begin to take place. Based on the unclear rationale to translate these studies from rodents to humans, the number of clinical trials investigating probiotics for the prevention colorectal cancer in humans is scarce. Once again, the results are inconsistent and conclusions regarding probiotic efficacy are difficult to draw.

Translating the use of probiotics to the real world is therefore tricky, with widespread prophylactic probiotic recommendations unlikely to be implemented over recommendations for a generally healthy lifestyle underpinned by low red meat consumption and high fibre diet. However, tailoring a probiotic strategy to high-risk Lynch syndrome carriers may be more warranted.

So what to do from here if you have Lynch syndrome? Stay tuned is the best advice. Maintain a good relationship with your GP, get routine surveillance and stay abreast of new and emerging research. Lynch Syndrome Australia is an excellent starting point. They provide updates on new best practice, emerging research findings and key policy decisions related to those with Lynch syndrome. If you suspect your family history may indicate an underlying genetic predisposition to cancer, the Lynch Syndrome Australia website also provides exceptional tools to help you decide if you and your family should consider genetic testing (see image below). They also offer exceptional patient information seminars, support networks and advice for dealing with a diagnosis or helping other seek the right support and counselling.

Finally, if you want to help support research in the area of Lynch syndrome, or are interested in volunteering, there are plenty of avenues to do so.

Lynch Syndrome Australia guide to determining if you family might have Lynch syndrome.

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