Interview by Zoe Garoufalia and Gloria Zaffaroni.

Lynch syndrome is characterised by predisposition to colorectal, endometrial, and other cancers, and is caused by autosomal dominant inherited pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. It is probably the most common predisposition to cancer. Despite its high estimated prevalence, up until now, there were no reliable long term data of MMR variant carriers in order to plan their treatment according to evidence-based medicine principles.

Toni SeppäläTherefore, in 2012, researchers from several collaborating European centres agreed to establish the Prospective Lynch Syndrome Database (PLSD) that is nowadays maintained and curated by European Hereditary Tumor Group (EHTG). The aims were to provide age and organ-specific cancer risks, according to gene and gender, estimates of survival after cancer and information on the effects of interventions. The key point is to change knowledge from retrospective to prospective studies.

Dr Toni Seppälä, who is colorectal surgeon at Helsinki University Hospital and currently a researcher at the Department of Surgical Oncology in Johns Hopkins University, introduces us to the revolutionary PLSD.

Dr Seppälä highlighted that the reason for establishing this database was:

‘the need to report more reliable long-term results of MMR gene variant carriers under surveillance and to increase knowledge about gene, gender, organ and age specific cancer risks’.

The first version of the PLSD included over 3000 patients from 10 countries. The primary findings, which were reported between 2015 and 2018, were that the organ specific cancer risks and penetrance of cancer varied based on the responsible gene present. Also, Dr Seppälä noted that:

‘the lifetime incidence of colorectal cancer was 50% for MLH1 and MSH2 carriers despite the surveillance colonoscopy programs’.

Ultimately, the expansion of the PLSD, now including 6350 patients from 18 countries, provided an even more accurate cancer risk estimate for each organ. The primary novel finding from this expansion, according to Dr Seppälä, was that the observed colorectal cancer risk was not substantially elevated in PMS2 carriers. This means that either endoscopic surveillance in those individuals was very effective or the monogenic PMS2 variants alone do not cause increased cancer risk.

‘We strikingly learned that perceptions that were based on small and retrospective studies and small national series were not very accurate’.

Another interesting finding, revealed from PLSD, was that surveillance colonoscopies did not prevent all colorectal cancers in these patients. The PLSD and another large study showed that cancer incidence was the same for annual or bi-annual surveillance colonoscopy as with cases where colonoscopy was performed every three years. He adds:

‘the point estimates for cancer incidence during very frequent colonoscopy surveillance are actually higher than those under less frequent surveillance, so there is a possibility of overdiagnosis of colorectal cancer’.

PLSD also made evident that there are at least three different pathways through which mismatch repair crypts develop into invasive carcinoma. Dr Seppälä also advises that:

‘The management of Lynch syndrome should be gene specific. The surveillance colonoscopies result in reduced cancer specific mortality but not so much in cancer incidence. There is no evidence base for yearly examinations in terms of incidence, stage or survival’.

In the future, PLSD, enriched with more patients, might help explain several other questions about Lynch Syndrome, such as why some carriers get more cancer types than others. Dr Seppälä underlines that since prevention relies mainly on aspirin consumption and lifestyle factors, and only to some extent from surveillance colonoscopies, MLH1 and MSH2 gene carriers may benefit from subtotal colectomy in terms of prevention of metachronous colorectal cancer.

The collaborators of PLSD stress the responsibility to show the evidence for benefit behind interventions, not recommend procedures as a precaution. Even when there is evidence of benefit, the costs, opportunity costs and adverse-effects of interventions should be considered in formulating clinical guidelines.

Finally to those who treat patients with Lynch Syndrome, Dr Seppälä recommends visiting the website. On this webpage, there are lifetime cancer risk calculators based on specific gene and gender characteristics. This helpful tool can be used in order to make individualized decisions and with the patient involvement, proceed in the best treatment pathway.

For more information about the PLSD and the future management of Lynch Syndrome read here.

Dr Toni Seppälä is colorectal surgeon at Helsinki University Hospital and adjunct professor in Surgery. Currently he is Research Fellow at Johns Hopkins University, at the Department of Surgical Oncology.

ESCP Affiliates