Risk factors for colorectal cancer and the impact on life in lynch syndrome

Colorectal cancer (CRC) constitutes the third most common cancer in Sweden. Approximately 2-4% of CRC cases have a pathogenic variant in a gene known to cause an inherited risk of CRC. The most common hereditary CRC syndrome, Lynch syndrome, is caused by germline pathogenic variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2 and in rare cases EPCAM. The lifetime risk of developing CRC in patients with Lynch syndrome is estimated to range between 30-70%. Due to the ranging risk of CRC, patients are not routinely offered prophylactic colectomy but rather surveillance by means of regular colonoscopies.

For study I, we aimed to describe different reasons leading to a genetic diagnosis of Lynch syndrome in the cohort of patients referred to Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance. Almost a third of patients were diagnosed with Lynch syndrome in association with cancer and that this proportion does not seem to have changed over time. This indicates a significant room for improvement regarding identification of Lynch syndrome patients before cancer develops.

For study II, whole exome sequencing was performed in members belonging to a Swedish family carrying a PMS2 missense mutation to study genetic CRC risk modifiers. The most interesting variant was a deletion in the gene BAG1. BAG1 has been linked to the progression of CRC by promoting CRC cell survival. We conclude from this study that the genetic architecture behind CRC development is complicated and to further study these mechanisms, it must be assessed in a genome wide manner.

Recommendations on colorectal surveillance in Lynch syndrome tend to differ according to different countries and guidelines. This is in large part due to the previously thought rare nature of Lynch syndrome, which makes it difficult to conduct studies with enough power to draw conclusions from and support recommendations. As more patients hopefully are diagnosed, surveillance is likely to be tailored to each patient. In study III, we evaluated the quality of endoscopic surveillance of the cohort referred to Karolinska University Hospital, Solna, Sweden. More specifically, we collected data regarding endoscopic surveillance to study the correlation between bowel preparation and adenoma detection (with known risk factors for CRC) as well as the correlation between CRC detection and surveillance interval length. Interval was not significant in CRC detection. We found no association between bowel preparation and the number of adenomas, though poor preparation was found to be associated with an older age and obesity, and a high number of detected adenomas was associated with older age, male sex and CRC detected during surveillance. The results indicate that special attention is needed for elderly, men and obese individuals regarding preparation and inspection.

For study IV, we conducted a scoping review to understand if and what type of research has been conducted to understand the impact on physical and mental health when living with a high risk of cancer. The impact on life seems to be higher in carriers of Lynch syndrome post-disclosure of a positive test but minimize over time. Worry in regards to children seems to be an especially prominent issue amongst patients. Patients express a lack of knowledge in healthcare services regarding Lynch syndrome, and cancer risk perception seems to influence approach to surveillance. Patients request more information regarding life after surgery.

List of scientific papers

I. Walton Bernstedt S, Björk J, Fritzell K, Spigelman AD, Björck E, Backman AS. Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer. Hered Cancer Clin Pract. 2021;19(1):18.
https://doi.org/10.1186/s13053-021-00171-4

II. Bryant P, Walton Bernstedt S, Thutkawkorapin J, Backman AS, Lindblom A, Lagerstedt-Robinson K. Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk. Eur J Cancer Prev. 2023;32(2):113-8.
https://doi.org/10.1097/CEJ.0000000000000769

III. Walton Bernstedt S, Haxhijaj A, Jamizadeh N, Björk J, Andreasson A, Forsberg A, Backman AS. Quality of endoscopic surveillance of Lynch syndrome patients in Stockholm, Sweden—adenoma detection and bowel cleanliness. Endosc Int Open.
https://doi.org/10.1055/a-2339-7152

IV. Walton Bernstedt S, Backman AS, Fritzell K. Impact on physical and mental health, and general well-being in Lynch syndrome patients: A scoping review. [Manuscript]