Lifestyle factors and colorectal cancer : incidence, prognosis and genetics

<p dir="ltr">Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. This thesis examines how lifestyle factors affect CRC development and prognosis, the changing CRC incidence and survival trends in Sweden, and the recurrence risk prediction models used to guide adjuvant chemotherapy recommendations.</p><p dir="ltr"><b>Study I</b> included 1,098 patients diagnosed with stage I-III CRC between 2003 and 2006. The exposure of interest was a healthy lifestyle, and the primary outcome was recurrence-free survival (RFS). Lifestyle data were self-reported using a semi-validated food frequency questionnaire. This data was used to calculate a healthy lifestyle and BMI (HL) score, categorizing participants into four groups, from the healthiest (4 points) to the least healthy (1 point). Follow- up data were collected from patient files, and survival analyses were conducted to assess recurrence-free survival across the four groups, each representing a different category of exposure, with the least healthy group serving as the reference. A healthy lifestyle was associated with a significant improvement in recurrence-free and overall survival.</p><p dir="ltr"><b>Study II</b> involved 616 cases of sporadic CRC with self-reported lifestyle risk factors and 1,642 healthy controls. Both cases and controls were genotyped using the OncoArray 500 K BeadChip. Five separate sliding-window haplotype GWAS analyses were conducted, all using the same set of healthy controls. Logistic regression was used to estimate the associations between haplotype regions and CRC in cases compared to controls. We identified 17 candidate susceptibility loci that were significantly associated with CRC. Several of these loci contained protein-coding regions of genes involved in inflammation, cell cycle regulation, and cancer development.</p><p dir="ltr"><b>Study III</b> was a nationwide registry-based study that included 135,610 incident CRC cases diagnosed in Sweden from 1993 to 2019. We used Poisson regression models to quantify incidence trends in early- versus late-onset CRC with annual percentage changes (APCs), and to assess differences in relative survival through excess mortality rate ratios (EMRRs). An increase in EOCRC incidence was observed across the right colon, left colon, and rectum during the study period. Right-sided colon cancer also increased among late-onset patients, while distal colon and rectal cancers decreased in this group starting in 2009. The EOCRC group had better stage-specific relative 5-year survival compared to late-onset patients. However, both groups experienced persistent excess mortality 5-10 years after diagnosis.</p><p dir="ltr"><b>Study IV</b> included 1,083 cases of stage I-III CRC diagnosed between 2003 and 2006. An experienced pathologist performed a detailed micromorphological assessment for each case according to protocol. Follow-up data were collected from patient files. Two logistic regression models were developed to assess the recurrence risk of cases, one of which included the emerging micromorphological risk factor tumor budding. In univariate analysis, budding was significantly associated with disease recurrence; however, this association was not observed in multivariate regression analyses. The predictive performance of the two models was compared using receiver operating characteristic (ROC) curves. Adding tumor budding to the established risk factors did not improve the prediction of recurrence risk.</p><h3>List of scientific papers</h3><p dir="ltr">I.<b> </b><b>Barot S;</b> Rantanen P; Nordenvall C; Lindforss U; Everhov AH; Larsson SC; Lindblom A; Liljegren A. Combined associations of a healthy lifestyle and body mass index with colorectal cancer recurrence and survival: a cohort study. Cancer Causes & Control, 2024;35(2): 367-376. <a href="https://doi.org/10.1007/s10552-023-01802-y" rel="noreferrer" target="_blank">https://doi.org/10.1007/s10552-023-01802-y</a></p><p dir="ltr">II.<b> </b><b>Barot S;</b> Vermani L; Blom J; Larsson S; Liljegren A; Lindblom A. Candidate Genetic Loci Modifying the Colorectal Cancer Risk Caused by Lifestyle Risk Factors. Clinical and Translational Gastroenterology, 2025;16(1):e00790. <a href=" https://doi.org/10.14309/ctg.0000000000000790" rel="noreferrer" target="_blank">https://doi.org/10.14309/ctg.0000000000000790</a></p><p dir="ltr">III.<b> Barot S;</b> Liljegren A; Nordenvall C; Blom J; Radkiewicz C. Incidence trends and long-term survival in early-onset colorectal cancer: a nationwide Swedish study. Annals of Oncology, 2025 ;: SO923- 7534(25)00920-2. <a href="https://doi.org/10.1016/j.annonc.2025.07.019" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.annonc.2025.07.019</a></p><p dir="ltr">IV. <b>Barot S;</b> Andersson-Franko M; Ghazi S; Lindforss U; Rantanen P; Blom J; Lindblom A; Liljegren A. Impact of Tumor Budding on Recurrence Risk Prediction in Stage I-III Colorectal Cancer: A Swedish Cohort study. [Submitted]</p>