Browsing by Subject "colorectal cancer"

Colorectal cancer (CRC) accounts for one in 10 new cancer cases worldwide. CRC risk is determined by a complex interplay of constitutional, behavioral, and environmental factors. Patients with ulcerative colitis (UC) are at increased risk of CRC, but effect estimates are heterogeneous, and many studies are limited by small numbers of events. Furthermore, it has been challenging to distinguish the effects of age at UC diagnosis and duration of UC. Multistate models provide a useful statistical framework for analyses of cancers and premalignant conditions. This thesis has three aims: to review the mathematical and statistical background of multistate models; to study maximum likelihood estimation in the illness-death model with piecewise constant hazards; and to apply the illness-death model to UC and CRC in a population-based cohort study in Finland in 2000–2017, considering UC as a premalignant state that may precede CRC. A likelihood function is derived for multistate models under noninformative censoring. The multistate process is considered as a multivariate counting process, and product integration is reviewed. The likelihood is constructed by partitioning the study time into subintervals and finding the limit as the number of subintervals tends to infinity. Two special cases of the illness-death model with piecewise constant hazards are studied: a simple Markov model and a non-Markov model with multiple time scales. In the latter case, the likelihood is factorized into terms proportional to Poisson likelihoods, which permits estimation with standard software for generalized linear models. The illness-death model was applied to study the relationship between UC and CRC in a population-based sample of 2.5 million individuals in Finland in 2000–2017. Dates of UC and CRC diagnoses were obtained from the Finnish Care Register for Health Care and the Finnish Cancer Registry, respectively. Individuals with prevalent CRC were excluded from the study cohort. Individuals in the study cohort were followed from January 1, 2000, to the date of first CRC diagnosis, death from other cause, emigration, or December 31, 2017, whichever came first. A total of 23,533 incident CRCs were diagnosed during 41 million person-years of follow-up. In addition to 8,630 patients with prevalent UC, there were 19,435 cases of incident UC. Of the 23,533 incident CRCs, 298 (1.3%) were diagnosed in patients with pre-existing UC. In the first year after UC diagnosis, the HR for incident CRC was 4.67 (95% CI: 3.07, 7.09) in females and 7.62 (95% CI: 5.65, 10.3) in males. In patients with UC diagnosed 1–3 or 4–9 years earlier, CRC incidence did not differ from persons without UC. When 10–19 years had passed from UC diagnosis, the HR for incident CRC was 1.63 (95% CI: 1.19, 2.24) in females and 1.29 (95% CI: 0.96, 1.75) in males, and after 20 years, the HR was 1.61 (95% CI: 1.13, 2.31) in females and 1.74 (95% CI: 1.31, 2.31) in males. Early-onset UC (age <40 years) was associated with a markedly increased long-term risk of CRC. The HR for CRC in early-onset UC was 4.13 (95% CI: 2.28, 7.47) between 4–9 years from UC diagnosis, 4.88 (95% CI: 3.46, 6.88) between 10–19 years, and 2.63 (95% CI: 2.01, 3.43) after 20 years. In this large population-based cohort study, we estimated CRC risk in persons with and without UC in Finland in 2000–2017, considering both the duration of UC and age at UC diagnosis. Patients with early-onset UC are at increased risk of CRC, but the risk is likely to depend on disease duration, extent of disease, attained age, and other risk factors. Increased CRC risk in the first year after UC diagnosis may be in part due to detection bias, whereas chronic inflammation may underlie the long-term excess risk of CRC in patients with UC.

Bacteria are dominant members of the human gut microbiota, defined as the complex communities of microorganisms in the intestine which play an important role in regulating the health of their host, including the development of colorectal cancer (CRC). CRC is the fourth leading cancer-related mortality worldwide. Animal models are very useful in CRC research, as they allow studying molecular mechanism underlying the disease. Due to closer similarity to human beings in terms of nutrition and gastrointestinal physiology, pig models are of great value in research when compared with murine models. However, our current knowledge of the pig gut microbiome is still limited and a large number of gut bacterial species are yet to be isolated and characterised. Here, we characterised bacteria isolated from the intestine of wildtype pigs and transgenic APC1311/+ siblings (APC pigs) that develop colonic adenomas. A total of 12 novel bacteria, including 1 member of a potentially novel family, were identified from 256 strains isolated using anaerobic culturing. In addition, five other bacteria with a standing name in the nomenclature but not yet included in the pig collection were added. A draft genome was generated for four of the novel bacteria and thereby the functional potential of strains and compared their similarity. In addition, the morphology, bile salt hydrolase (BSH), 7α-dehydroxylation, carbohydrate fermentation, prevalence and abundance of all strains were analysed. The draft genome analysis confirmed the novel species status of the four bacteria. Furthermore, it also revealed the presence of genes associated with BSH, antibiotic resistance, butyrate production and carbohydrate utilization. Only two of 12 tested bacteria were positive for BSH, while none of the two bacteria selected for fermentation experiments was positive for 7α-dehydroxylation. One isolate of the species Paraclostridium benzoelyticum was found to exhibit significantly higher tolerance to NaCl than the same species described in the literature. In terms of prevalence, almost all of the bacteria (16 of 17) seem to be rare in pig, even though they appeared to be more enriched in the pig intestine when compared with other host species. Interestingly, the majority of positive samples for the bacterium representing the potentially novel family originated from the intestine of elderly human individuals. Overall, we could show that a substantial number of novel bacteria can still be isolated by classical anaerobic culture techniques using multiple rich or selective media. Even though we were able to identify most of the isolated bacteria and performed several assays to describe their properties, additional phylogenetic and taxonomic tests and development of optimal media/conditions for the novel bacteria are required in order to gain a deeper understanding of the role of these bacteria in the intestinal microbial ecosystem.

Ihmisellä suolistosyöpää esiintyy eniten paksusuolessa. Suolistosyöpätapauksien määrä on lisääntynyt jatkuvasti, tehden siitä kolmanneksi yleisimmän ja toiseksi eniten kuolemaan johtavan syöpätyypin. Vuonna 2020 maailmanlaajuisesti todettiin noin 2 miljoonaa uutta suolistosyöpätapausta, ja Suomessa vastaava luku oli noin 3000. Lisääntynyt ymmärrys suolistosyövästä ja sen hoitovaihtoehtojen parantumisesta on vähentänyt kuolleisuutta suolistosyöpään, mutta elämänkaaren pidentyminen ja elintapojen muutos on johtanut esiintyvyyden nousuun. Suolistosyövän esiintyvyys lisääntyy merkittävästi yli 60 ikävuoden jälkeen. Sille altistavia tekijöitä ovat liikunnan vähyys, ylipaino, ikääntyminen sekä epäterveellinen ruokavalio. WNT-signalointireitti säätelee mm. organismin kehitystä ja kudoksien homeostaasia. LEF1 (Lymphoid enchancer binding factor 1) on transkriptiotekijä, joka vaikuttamaan geenien toimintaan WNT-signaalien alaisuudessa. LEF1 ei ole aktiivinen normaalisuolen epiteelissä, mutta sen poikkeuksellinen ekspressio aktivoituu syövän kehittyessä. Aiempien tutkimusten mukaan Lef1 geenin poisto hiiristä kiihdyttää solujen kasvua suolistosyövän adenooma-esiasteissa. Tällä tutkimuksella oli tarkoitus tutkia tarkemmin LEF1 vaikutusmekanismia suolistosyövän kehityksen alkuvaiheessa, kasvaimen klonaalisen laajentumisen aikana. Tutkimus toteutettiin geenimuokatuissa hiirissä. Tulokset osoittavat, että LEF1 ei osallistu suolistosyövän kehityksen rajoittamiseen kasvaimen alkuvaiheessa.

Colorectal cancer (CRC) is the second deadliest cancer in the world. Given the heterogeneity of the disease, a substantial percentage of patients do not benefit from the standard-of-care. The ability to identify patients that most or least likely to respond to the generic therapy prior to its implementation would improve the safety and efficacy of the anti-cancer regimen in CRC.The goal of this study was to assess the suitability of patient-derived organoids (PDOs) as in vitro models to evaluate the efficacy of chemotherapy in CRC. PDOs were generated from surgical tumor specimens of rectal cancer patients. Next, PDOs were treated with standard of care chemotherapeutics for rectal cancer, with or without neoadjuvant radiotherapy, and a commercial cell viability assay was used to assess drug response. PDOs were classified according to the consensus molecular subtype (CMS) system, based on the whole transcriptome sequencing of PDO-derived RNA before treatment. Clinical information was retrieved from the patient records. In vitro drug responses of PDOs revealed heterogeneous drug sensitivity profiles and highlighted patients who would benefit from standard of care. With respect to the consensus molecular subtype (CMS) classification, CMS2 organoids showed highest response to standard of care, while CMS1 PDOs exhibited a less responsive phenotype. For the majority of the PDOs, neoadjuvant radiotherapy prior to drug treatment had no effect on drug response. On the other hand, in certain cases, neoadjuvant therapy sensitized or desensitized PDOs to standard of care chemotherapeutics. This study adds to the literature demonstrating the feasibility of PDOs as platforms for modelling cancer treatment and highlighting their potential to facilitate progress in personalized medicine. More studies involving complex, co-culture PDO models and designed to better reflect the relevant interplay between tumor microenvironment and the anti-cancer regimen are needed to confirm the predictive qualities of the PDOs and inform clinical decisions in CRC.

This population-based registry study aimed to report 30-day and one-year postoperative survival, five-year overall survival (OS), and disease-specific survival (DSS) among elderly (≥75 years old) colorectal cancer (CRC) patients. All new colorectal cancer cases from 2006–2015 were included and followed until death or the end of follow-up (end of 2016). Among 27 088 CRC patients, 11 306 patients were ≥75 years old. Among patients ≥75 years, 36.8% (n = 4160) had right-sided colon cancer, 21.9% (n = 2478) left-sided colon cancer, and 32.3% (n = 3650) rectal cancer. In this study population, 932 patients were aged ≥90. The 30-day postoperative OS for patients aged 75–79 was 96.1% (95% confidence interval [CI] 95.3–96.9) falling to 93.2% (95% CI 92.0–94.4) for patients aged 80–84. The one-year postoperative OS among patients aged 75–79 was 86.3% (95% CI 84.7–87.9) compared with 80.5% (95% CI 78.7–82.3) among patients aged 80–84. Five-year OS among patients aged 75–79 was 47.6% (95% CI 46.0–49.2) and 36.6% (95% CI 34.8–38.4) among patients aged 80–84, compared with 61.7% (95% CI 60.9–62.5) among younger patients (<75 years old). Survival among elderly CRC patients (≥75 years old) was in general fairly good when compared with younger patients, especially among patients aged 75–79 and 80–84 with localized or locally advanced disease.

Colorectal cancer (CRC) is one of the most common types of cancers, encompassing approximately 10 % of all cancer cases worldwide. Regulation of cell proliferation and cell fate decisions is crucial for maintaining cellular homeostasis and preventing CRC initiation, a process in which the Wingless (Wnt)/β-catenin signalling pathway is known to play an important role. For instance, somatic mutations occurring in the Apc gene lead to aberrant activation of the Wnt/β-catenin pathway, which further leads to the accumulation of β-catenin into the nucleus where the TCF/LEF transcription factors, including TCF1, TCF3, TCF4, and LEF1, bind β-catenin to activate downstream Wnt target genes and promote CRC development. TCF1 is encoded by the gene Tcf7 that can be alternatively spliced to produce long (p45) and short (p33) isoforms whose function in CRC development has remained poorly understood. Previously, deletion of Tcf7 has been found to increase intestinal adenoma formation in mice with one mutated Apc allele (ApcMin/+), which are predisposed to development of multiple intestinal adenomas. To study how heterozygous deletion of the p45 isoforms affects intestinal adenoma formation and the cellular transcriptome, we have studied ApcMin/+ mice, which have a heterozygous mutation of Tcf7 gene encoding only the p33 isoform (AmTp45∆/+). In our study, we used immunohistochemistry and RT-qPCR together with a single-cell RNA sequencing (scRNA-seq) analysis. Heterozygous deletion of the p45 isoforms in the ApcMin/+ mice dramatically increased the numbers of intestinal tumours, spleen size and its white pulp areas but it had no effect on cell proliferation or expression of the Wnt-target gene Prox1 in intestinal adenomas. In addition, ApcMin/+ mice with both heterozygous p45 and Lef1 deletions developed significantly more intestinal tumours. Without the Apc mutation, neither of these mouse models developed intestinal adenomas or spleen abnormalities. RT-qPCR analysis showed decreased expression of Tcf7 in the small intestine of the AmTp45∆/+ mice. scRNA-seq analysis revealed that the AmTp45∆/+ mice downregulated various Wnt antagonists and stem cell markers and upregulated several genes that function in different metabolic pathways. Overall, these results support the concept that Tcf7 functions in synergy with Apc to repress intestinal malignancy. Our results establish a basis for comparison of the relative importance and specific functions of the TCF/LEF1 family members in CRC development.