Early onset colorectal cancer in Canterbury, New Zealand.

BACKGROUND: The overall incidence of colorectal cancer is decreasing in much of the world, yet the incidence in those under 50 years of age is increasing (early onset colorectal cancer (EOCRC)). The reasons for this are unclear. This study was undertaken to describe the clinical, pathological and familial characteristics of patients with EOCRC and their oncological outcomes and compare this with previously published data on late onset colorectal cancer (LOCRC). METHODS: A retrospective review of all patients diagnosed with EOCRC in Canterbury between 2010 and 2017 was conducted. Data was collected on demographics, family history, treatment, and oncologic outcomes. Kaplan-Meier survival curves were calculated to assess overall survival based on disease stage. RESULTS: During the study period (2010-2017) there were 3340 colorectal cancers diagnosed in Canterbury, of which 201 (6%) were in patients under 50 years (range: 17-49). Of these, 87 (43.3%) were female and 125 (62.2%) were aged between 40 and 49 years. 28 (13.9%) were associated with hereditary conditions. Of the 201 patients, 139 (69.2%) had rectal or left-sided cancers. 142 (70.6%) patients presented with either stage 3 or 4 disease and the 5-year overall survival by stage was 79.1% and 14.4%, respectively. CONCLUSION: EOCRC is increasing and usually presents as distal left sided cancers, and often at an advanced stage. They do not appear to have the common risk factors of family history or inherited pre-disposition for colorectal cancer. Planning by healthcare providers for this epidemiological change is imperative in investigating symptomatic patients under 50 and optimizing early detection and prevention.

Vitamin D receptor polymorphisms in colorectal cancer in New Zealand: an association study.

AIM: Polymorphisms of the vitamin D receptor (VDR) gene may be a risk factor for colorectal cancer (CRC). We investigated the association of three single nucleotide polymorphisms (SNPs) of the VDR gene with CRC in age and gender matched patients and controls of European origin in New Zealand. METHOD: CRC (N=200) and healthy control (N=200) samples were genotyped for the Fok1 (rs2228570), Taq1 (rs731236) and Cdx2 (rs11568820) polymorphisms using Taqman® SNP genotyping assays. Chi-squared analysis was used to test for overall association of VDR genotype with disease, and by age and gender subgroups. RESULTS: There were no significant associations of the three VDR SNPs with disease either by allelic frequencies (p=0.43-0.73) or genotypic distribution (p=0.15-0.90). Furthermore, no significant differences for allelic frequencies of the three SNPs were revealed in subgroup analysis by age (above/below median age of 72 yrs; p=0.38-0.91), gender (p=0.22-0.88), or age/gender (p=0.33-0.93) CONCLUSION: We found no evidence to suggest that the VDR SNPs Fok1, Taq1 and Cdx2 influence CRC risk in New Zealand Europeans.

NOD2 and ATG16L1 polymorphisms affect monocyte responses in Crohn's disease.

AIM: To assess whether polymorphisms in NOD2 and ATG16L1 affect cytokine responses and mycobacterium avium subspecies paratuberculosis (MAP) survival in monocytes from Crohn's disease (CD) patients. METHODS: Monocytes were isolated from peripheral blood of CD patients of known genotype for common single nucleotide polymorphisms of NOD2 and ATG16L1. Monocytes were challenged with MAP and bacterial persistence assessed at subsequent time-points. Cytokine responses were assayed using a Milliplex multi-analyte profiling assay for 13 cytokines. RESULTS: Monocytes heterozygous for a NOD2 polymorphism (R702W, P268S, or 1007fs) were more permissive for growth of MAP (P = 0.045) than those without. There was no effect of NOD2 genotype on subsequent cytokine expression. The T300A polymorphism of ATG16L1 did not affect growth of MAP in our model (P = 0.175), but did increase expression of cytokines interleukin (IL)-10 (P = 0.047) and IL-6 (P = 0.019). CONCLUSION: CD-associated polymorphisms affected the elimination of MAP from ex vivo monocytes (NOD2), or expression of certain cytokines (ATG16L1), implying independent but contributory roles in the pathogenesis of CD.

Incidence of Mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with Crohn's disease and control subjects.

OBJECTIVE: To define the incidence of Mycobacterium avium subspecies paratuberculosis (MAP) in patients with Crohn's disease (CD) and in control subjects. METHODS: Blood samples from 361 CD patients from a previously described population-based inflammatory bowel disease (IBD) cohort and 200 blood donor controls, of known NOD2 genotype, were screened by PCR for MAP-specific IS900 DNA. These results were correlated with NOD2 genotype. RESULTS: The PCR assay was capable of detecting 20 fg of purified MAP DNA, equivalent to roughly 100 MAP cells/mL of blood. MAP-specific IS900 DNA was detected in 33.8% of CD cases and 21.5% of controls (OR 1.86, 95% CI 1.247-2.785, P= 0.002). All study participants were genotyped for the NOD2 mutations 2104C>T (R702W), 2722G>C (G908R), and 3020insC (1007fs). Carriage of one or two NOD2 mutations was not associated with a significantly higher risk of CD (OR 0.75, 95% CI 0.465-1.207, P= 0.234). No significant association was seen in the CD cohort for carriage of one or two NOD2 mutations and MAP status (OR 0.883, 95% CI 0.494-1.579, P= 0.675). CONCLUSIONS: Screening peripheral blood using IS900 PCR indicated that MAP DNA could be detected in a significant proportion of CD cases from a large population-based cohort, and also, in control subjects. The over-representation of MAP DNA in CD suggests either a role or a probable role for MAP in the etiology of CD.

Adriamycin disruption of the Shh-Gli pathway is associated with abnormalities of foregut development.

BACKGROUND: The hedgehog signalling pathway appears to have a crucial role in the embryogenesis of the foregut in vertebrates. Sonic hedgehog (Shh) protein and gene are involved in the differentiation of many organ systems such as notochord, floor plate, and limbs; development of the left-right axis in vertebrates; and differentiation of trachea and esophagus from the primitive foregut. METHODS: The prenatal exposure of Sprague-Dawley fetal rats to Adriamycin between days 6 and 9 of gestation was used to induce esophageal atresia and tracheoesophageal fistula. Embryos were harvested by cesarean section on gestational days 11 to 15. Embryos were examined by microscopy, dissection, and serial histology. In situ hybridization was used to study Shh gene expression in the rat embryos. RESULTS: In situ hybridization showed that the pattern and level of Shh gene expression are affected by Adriamycin. Adriamycin-treated rats have deformed notochord and undivided foregut, and some of the embryos had a lack of the dorso-ventral patterning of Shh expression seen in control embryos. CONCLUSIONS: These results are consistent with the hypothesis that Adriamycin influences the Shh signalling pathway, resulting in disruption of normal development of the foregut.

Differences in the levels of Sonic hedgehog protein during early foregut development caused by exposure to Adriamycin give clues to the role of the Shh gene in oesophageal atresia.

Sonic hedgehog (Shh) protein is a signalling molecule that is important for defining patterning in the development of vertebrates. Shh has been shown to be involved in the morphogenesis of many organ systems such as notochord, floor plate and limbs and in the development of the left-right axis in vertebrates. In this study we show that high levels of protein occur during the initial period of foregut differentiation into trachea and oesophagus, and that low levels of Shh protein are seen during early development of the foregut where oesophageal atresia and/or tracheo-oesophageal fistula ensue. These studies show that Shh protein is expressed in the rat foregut during embryogenesis, and its level declines as the embryo approaches birth. In adriamycin-treated rats the level of Shh protein expression is very low without any time-dependent changes. These results are consistent with the hypothesis that adriamycin influences the Shh signalling pathway, resulting in disruption of normal development of the foregut.