ORCID Profile
0000-0002-2041-8602
Current Organisation
Flinders University
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Publisher: Elsevier BV
Date: 10-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.E15533
Abstract: e15533 Background: Assays for circulating tumor DNA (ctDNA) have shown utility for cancer detection and management. It is important to demonstrate cancer specificity of targeted ctDNA biomarkers. Detection of methylated BCAT1 and IKZF1 ctDNA has shown high sensitivity for colorectal cancer (CRC). The aim of this study was to investigate whether hypermethylation of these two biomarkers is also present in prostate or breast adenocarcinoma (PCa or BCa) tissues, and if they are detectable as ctDNA from such cancer patients. Methods: A subset of TCGA data comprising matched tumor and normal s les from PRAD (n = 50), BRCA (n = 90) and COADREAD (n = 44) cohorts were accessed to interrogate DNA methylation (450K) at CpG probes covered by the BCAT1/ IKZF1 ctDNA assay (cg10764357 and cg07589773/cg18607529, respectively). Linear regression of BCAT1/ IKZF1 methylation and tumor staging was performed for cases with AJCC staging data (PRAD n = 503 BRCA n = 788 COADREAD n = 284). Blood was collected from BCa (n = 32) or PCa (n = 101) patients prior to starting treatment at Flinders Medical Centre (South Australia). DNA isolated from plasma was bisulphite-converted and assayed for BCAT1/ IKZF1 methylation. Age-adjusted comparisons of ctDNA positivity were made with blood results from N = 310 pre-treatment CRC patients (60% male), as well as male (N = 344) and female (N = 383) controls with a clear colonoscopy and no history of cancer. Results: BCAT1 and IKZF1 were significantly hypermethylated in PCa and CRC tumors compared to matched normal tissues (Table). Conversely, BCAT1/ IKZF1 CpG probes were hypomethylated in breast tumors compared to matched normal s les. There was no correlation between hypermethylation in IKZF1/ BCAT1 and stage of PCa or CRC. In contrast to PCa in silico findings of hypermethylation, BCAT1/IKZF1 ctDNA methylation was only positive in 7/101 PCa blood s les (6.9% 95%CI 3.2-13.9%). Three of 32 BCa blood s les (9.4% 95%CI 2.5-25%) were positive for BCAT1/IKZF1 methylation. These positivity rates were not significantly different to controls at 8.5% for females (p = 0.80 vs BCa) and 8.2% for males (p = 0.73 vs PCa), but all were significantly lower than that observed in CRC cases (59.0%, 183/310 p 0.001). Conclusions: While interrogation of TCGA datasets revealed IKZF1 and BCAT1 hypermethylation in prostate tumors, detection rate of these biomarkers in blood from PCa patients was not higher than that of non-cancer controls. Likewise, the BCAT1/IKZF1 ctDNA assay positivity rate in BCa patients was also no different to non-cancer controls. These findings highlight the specificity of methylated BCAT1 and IKZF1 ctDNA for detection of CRC.[Table: see text]
Publisher: Elsevier BV
Date: 12-2022
Publisher: Elsevier BV
Date: 08-2023
Publisher: Wiley
Date: 10-2013
Abstract: Red meat is considered a risk factor for colorectal cancer (CRC). Heme is considered to promote colonic hyperproliferation and cell damage. Resistant starch (RS) is a food that ferments in the colon with studies demonstrating protective effects against CRC. By utilizing the western diet model of spontaneous CRC, we determined if feeding heme (as hemin chloride) equivalent to a high red meat diet would increase colonic DNA adducts and CRC and whether RS could abrogate such effects. Four groups of mice: control, heme, RS and heme + RS were fed diets for 1 or 18 months. Colons were analyzed for apoptosis, proliferation, DNA adducts "8-hydroxy-2-deoxyguanosine" and "O(6) -methyl-2-deoxyguanosine" (O(6) MeG), and neoplasms. In the short term, heme increased cell proliferation (p < 0.05). Changes from 1 to 18 months showed increased cell proliferation (p < 0.01) and 8-hydroxy-2-deoxyguanosine adducts (p < 0.05) in all groups, but only heme-fed mice showed reduced apoptosis (p < 0.01) and increased O(6) MeG adducts (p < 0.01). The incidence of colon neoplasms was not different between any interventions. We identified heme to increase proliferation in the short term, inhibit apoptosis over the long term, and increase O(6) MeG adducts in the colon over time although these changes did not affect colonic neoplasms within this mouse model.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2010
DOI: 10.1038/ONC.2009.449
Abstract: There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy s les were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at 'type A' (ESR1, GATA5, HIC1, HPP1, SFRP1) and 'type C' markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. 'Type A' genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. 'Type C' methylation is more specific for neoplasia. The last five 'type C' markers comprise a CIMP panel. The mean 'type A' and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most 'type A' genes showed direct correlations between methylation and age (ESR1, rho=0.66, P<0.0001), with higher methylation distally (ESR1, P<0.0001). On multivariate analysis, 'type A' methylation was inversely associated with colorectal adenomas (odds ratio=0.23, P<0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio=5.1, P=0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000381675
Abstract: Red meat may increase promutagenic lesions in the colon. Resistant starch (RS) can reduce these lesions and chemically induced colon tumours in rodents. i Msh2 /i is a mismatch repair (MMR) protein, recognising unrepaired promutagenic adducts for removal. We determined if red meat and/or RS modulated DNA adducts or oncogenesis in i Msh2 /i -deficient mice. A total of 100 i Msh2 /i sup i -/- /i /sup and 60 wild-type mice consumed 1 of 4 diets for 6 months: control, RS, red meat and red meat + RS. Survival time, aberrant crypt foci (ACF), colon and small intestinal tumours, lymphoma, colonic O sup /sup -methyl-2-deoxyguanosine (O sup /sup MeG) adducts, methylguanine methyltransferase (MGMT) and cell proliferation were examined. In i Msh2 /i sup i -/- /i /sup mice, red meat enhanced survival compared to control (p 0.01) and lowered total tumour burden compared to RS (p 0.167). i Msh2 /i sup i -/- /i /sup mice had more ACF than wild-type mice (p 0.014), but no colon tumours developed. i Msh2 /i sup i -/- /i /sup increased cell proliferation (p 0.001), lowered DNA O sup /sup MeG adducts (p 0.143) and enhanced MGMT protein levels (p 0.001) compared to wild-type mice, with RS supplementation also protecting against DNA adducts (p 0.01). No link between red meat-induced promutagenic adducts and risk for colorectal cancer was observed after 6 months' feeding. Colonic epithelial changes after red meat and RS consumption with MMR deficiency will differ from normal epithelial cells.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2022
DOI: 10.1200/JCO.2022.40.4_SUPPL.348
Abstract: 348 Background: Esophagogastric cancers (EG cancers) are associated with high mortality and poor treatment outcomes due to advanced disease at diagnosis. Reliable non-invasive biomarkers are lacking for detection and prognostication. The aim of this study was to assess the clinical utility of methylated BCAT1 and IKZF1 circulating tumour DNA (ctDNA) for detection and prognosis of EG cancers. Methods: Blood s les were collected from patients diagnosed with either esophageal or gastric adenocarcinoma prior to commencing any treatment. DNA was extracted from plasma and analysed for methylation of BCAT1 and IKZF1, and ACTB as the reference gene, by multiplex qPCR. ctDNA positivity rates were assessed against cancer clinicopathological features using chi-squared tests and age-adjusted logistic regression with odds ratios (OR). Secondary outcome was overall survival after 12 months using cox-proportional hazard ratio (HR). Results: Ninety-seven patients (77/97 (79%) male 70 (72%) with esophageal cancer and 27 (28%) with gastric cancer) were enrolled with median age 72 years (IQR = 61-79). Fifty-three (55%) were ctDNA positive. There was no difference between the ctDNA positivity rate of esophageal and gastric cancers (p 0.05). Positivity was significantly associated with node positive tumours (N0 = 6/23 (20.7%), N1 = 5/10 (50%), N2 = 11/17 (64.7%), N3 = 3/4 (75%) p = 0.01) and depth of invasion (T1 = 0/9 (0%), T2 = 5/12 (41.7%), T3 = 17/36 (47.2%), T4 = 5/6 (83.3%), p = 0.049). ctDNA positivity was independent of history of GORD or Barrett’s disease (p 0.05). There was a significant association between ctDNA and advanced stage disease (Stage I = 1/13 (7.7%), Stage II = 2/12 (16.7%), Stage III = 25/40 (62.5%), Stage IV = 25/32 (78.1%)), with stage IV cases having a 43-fold increased odds for a positive ctDNA result compared to stage I (OR = 43.1, 95%CI 4.7-392.0 p = 0.001). Patients testing positive for ctDNA had poorer overall survival outcomes compared to those testing negative (HR 4.23, 95% CI 1.84-9.68, p 0.001). Conclusions: Our study demonstrates a potential role for methylated BCAT1 and IKZF1 ctDNA as a biomarker for the detection of EG cancers. The detection of ctDNA is significantly associated with poorer survival outcomes, with further studies warranted to determine whether ctDNA can be an independent predictor of survival. The integration of this ctDNA assay into clinical practice could further improve risk stratification, which may guide treatment strategies.
Publisher: EpiSmart Science Vector Ltd
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 16-07-2011
DOI: 10.1007/S10620-010-1312-4
Abstract: DNA methylation varies throughout the normal colorectal mucosa and DNA methylation in normal appearing mucosa is associated with serrated and adenomatous neoplasia elsewhere within the colorectum. The purpose of this study was to measure luminal chemistry, rectal proliferation and mucosal DNA methylation and thus determine whether regional and pathological patterns of DNA methylation could be explained by luminal and epithelial factors. Twenty healthy subjects had normal rectal mucosal biopsies and a 24-h fecal collection. Rectal biopsies were analyzed for epithelial proliferation (Ki67 immunohistochemistry) and DNA methylation at 17 different markers, including "type A" markers (ESR1, GATA5, HIC1, HPP1, SFRP1), "type C" markers (MGMT, MLH1, CDKN2A, MINT1, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Fecal analysis included short-chain fatty acids (SCFA), pH and ammonia. Mean "type A" and CIMP panel methylation Z-scores were calculated. Rectal proliferation was significantly correlated with methylation at ESR1 (ρ = 0.81, P = 0.003) and GATA5 (ρ = 0.78, P = 0.012). LINE-1 methylation was 71.7 vs. 74.1%, in patients with "low" and "high" fecal total SCFA concentration (defined by the median value), respectively (P = 0.0019). On multivariate linear regression "type A" methylation was independently associated with rectal proliferation (P = 0.001). LINE-1 methylation was directly associated with rectal proliferation (P = 0.038) and total fecal SCFA concentration (P = 0.002), and inversely associated with fecal NH(3) concentrations (P = 0.003). DNA methylation in normal rectal mucosa is associated with crypt proliferation and fecal SCFA concentration. These associations may help to explain regional differences in DNA methylation as well as providing a possible link between the colorectal lumen and carcinogenesis.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2013
DOI: 10.1007/S10620-013-2844-1
Abstract: Although a genetic component has been identified as a risk factor for developing inflammatory bowel disease, there is evidence that dietary factors also play a role in the development of this disease. The aim of this study was to determine the effects of feeding a red meat diet with and without resistant starch (RS) to mice with dextran sulfate sodium (DSS)-induced colitis. Colonic experimental colitis was induced in Balb/c mice using DSS. The severity of colitis was evaluated based on a disease activity index (based on bodyweight loss, stool consistency, rectal bleeding, and overall condition of the animal) and a histological score. Estimations were made of numbers of a range of different bacteria in the treatment pools of cecal digesta using quantitative real-time PCR. Consumption of a diet high in red meat increased DSS-induced colitis as evidenced by higher disease activity and histopathological scores. Addition of RS to the red meat diet exerted a beneficial effect in acute DSS-induced colitis. Subjective analysis of numbers of a range of bacterial targets suggest changes in the gut microbiota abundance were induced by red meat and RS treatments and these changes could contribute to the reported outcomes. A dietary intake of red meat aggravates DSS-induced colitis whereas co-consumption of resistant starch reduces the severity of colitis.
Publisher: Elsevier BV
Date: 2017
Publisher: American Chemical Society (ACS)
Date: 10-03-2023
DOI: 10.1021/JACS.2C11446
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.CELREP.2020.108585
Abstract: Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer s les, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
Publisher: BMJ
Date: 05-2022
DOI: 10.1136/BMJOPEN-2021-060712
Abstract: Colorectal cancer (CRC) is the third most diagnosed cancer and the second most common cause of cancer mortality worldwide. Most CRCs develop through either the adenoma-to-carcinoma or the serrated pathways, and, therefore, detection and removal of these precursor lesions can prevent the development of cancer. Current screening programmes can aid in the detection of CRC and adenomas however, participation rates are suboptimal. Blood-based biomarkers may help to address these low participation rates in screening programmes. Although blood-based biomarker tests show promise for cancer detection, limited attention has been placed on the sensitivity and specificity for detection of the precursor lesions. The aim of this research is to conduct a systematic review and meta-analysis to evaluate the accuracy of blood-based biomarker tests in detecting advanced precancerous lesions. This protocol was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols (PRISMA-P) and results will be reported in line with the PRISMA guidelines. Literature searches will be conducted on PubMed, Embase and Web of Science. Two reviewers will conduct the searches, and independently screen them, according to title and abstract and then the full-text versions of those selected articles as well as the risk of bias via the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) tool. The Grading of Recommendations Assessment, Development and Evaluation guidelines will be used to validate the certainty of evidence for recommendations based on the risk of bias findings. Meta-analysis will be conducted where appropriate on groups of studies with low heterogeneity. No patient data will be included in our review and, therefore, ethics approval is not required. It is anticipated that the review will identify the most promising candidate biomarkers for clinical translation in the screening of advanced precancerous lesions. The results will be published in a peer-reviewed journal. CRD42021285173.
Publisher: Oxford University Press (OUP)
Date: 19-02-2016
Abstract: This study evaluated whether dietary resistant starch (RS) and green tea extract (GTE), which have anti-inflammatory and anticancer properties, protect against colitis-associated colorectal cancer (CAC) using a rat model, also investigated potential mechanisms of action of these agents including their effects on the gut microbiota. Rats were fed a control diet or diets containing 10% RS, 0.5% GTE or a combination of the two (RS + GTE). CAC was initiated with 2 weekly azoxymethane (AOM) injections (10mg/kg) followed by 2% dextran sodium sulphate in drinking water for 7 days after 2 weeks on diets. Rats were killed 20 weeks after the first AOM. Colon tissues and tumours were examined for histopathology by H&E, gene rotein expression by PCR and immunohistochemistry and digesta for analyses of fermentation products and microbiota populations. RS and RS + GTE (but not GTE) diets significantly (P< 0.05) decreased tumour multiplicity and adenocarcinoma formation, relative to the control diet. Effects of RS + GTE were not different from RS alone. RS diet caused significant shifts in microbial composition/ ersity, with increases in Parabacteroides, Barnesiella, Ruminococcus, Marvinbryantia and Bifidobacterium as primary contributors to the shift. RS-containing diets increased short chain fatty acids (SCFA) and expression of the SCFA receptor GPR43 mRNA, and reduced inflammation (COX-2, NF-kB, TNF-α and IL-1β mRNA) and cell proliferation P< 0.05. GTE had no effect. This is the first study that demonstrates chemopreventive effects of RS (but not GTE) in a rodent CAC model, suggesting RS might have benefit to patients with ulcerative colitis who are at an increased risk of developing CRC.
Publisher: Wiley
Date: 16-03-2022
DOI: 10.1111/JGH.15823
Abstract: Surveillance colonoscopies may be delayed because of pressure on resources, such as the COVID‐19 pandemic. This study aimed to determine whether delayed surveillance colonoscopy increases the risk for advanced neoplasia and whether interval screening with faecal immunochemical tests (FITs) and other known risk factors can mitigate this risk. A retrospective cohort study of in iduals undergoing surveillance colonoscopy for personal or family history of colorectal neoplasia was being provided with FIT between colonoscopies. Colonoscopy ≥ 6 months after the guideline‐recommended interval was considered “delayed.” In iduals were stratified based on prime colonoscopy findings to nonneoplastic findings, non‐advanced adenoma, and advanced adenoma. The relative risk (RR) for developing advanced neoplasia was determined using a robust multivariable modified Poisson regression. Of 2548 surveillance colonoscopies, 1457 (57.18%) were delayed. Prior advanced adenoma, older age ( 60 years) and nonparticipation in interval FIT were associated with increased risk for advanced neoplasia ( P 0.05). There was a trend to increased risk in those with prior advanced adenoma with an increasing colonoscopy delay ( P trend = 0.01). In participants who did not complete interval FIT and having advanced adenoma in the prime colonoscopy, risk of advanced neoplasia was 2.48 times higher (RR = 2.48, 95% confidence interval: 1.20–5.13) in participants who had beyond 2 years of delayed colonoscopy compared with those with on‐time colonoscopy. Colonoscopy delay did not increase the risk of advanced neoplasia in participants with negative interval FIT results. Surveillance colonoscopy can be safely extended beyond 6 months in elevated colorectal cancer risk patients who do not have prior advanced adenoma diagnosis, particularly if interval FIT is negative.
Publisher: Informa UK Limited
Date: 24-12-2009
DOI: 10.3109/15376510903521232
Abstract: This study compared the effects of three anti-mutagenic lichen extracts on colorectal oncogenesis in azoxymethane (AOM)-treated mice and determined whether the extracts also regulated the homeostatic response to genotoxic damage. C57BL/6J mice (n = 12 per group) were treated with the lichen extracts Antimutagen-He (AMH): AMH-C, AMH-D, or AMH-E dimethyl sulfoxide (DMSO, control) for 2 weeks. At the end of the treatment, mice were given a single AOM injection to induce DNA damage and killed 6 h later for measuring apoptosis and proliferation. Apoptotic and proliferation indexes in mice treated with AMH-C, AMH-D, and AMH-E were 0.61%, 1.41%, and 0.77% and 30.62%, 21.93%, and 27.27%, respectively, which were significantly lower than those of control mice (5.88% and 38.69%) (p < 0.05). To examine the effects of lichen extracts on colorectal cancer, separate groups of mice (n = 25 per group) treated with AMH-C, AMH-D, AMH-E, or DMSO were given 4-weekly AOM injections to induce oncogenesis. Mice were killed 24 weeks after the last AOM injection for assessing colon tumor formation. Colonic tumor incidences were 47.3%, 13%, and 20% the tumor volumes were 18.47, 2.75, and 10.78 mm(3), respectively, in mice treated with AMH-C (p < 0.05), AMH-D (p 0.05), compared to 24% and 13.28 mm(3) in mice of control correspondingly. No lichen extract showed evident toxic effects on mice. No usnic acid was found in these lichen extracts. The regulation of acute apoptosis and cell proliferation in colonic epithelial cells and the anti-mutagenesis do not seem directly related to the cancer protective effect.
Publisher: Cambridge University Press (CUP)
Date: 17-06-2015
DOI: 10.1017/S0007114515001750
Abstract: Epidemiological studies have identified increased colorectal cancer (CRC) risk with high red meat (HRM) intakes, whereas dietary fibre intake appears to be protective. In the present study, we examined whether a HRM diet increased rectal O 6 -methyl-2-deoxyguanosine (O 6 MeG) adduct levels in healthy human subjects, and whether butyrylated high-amylose maize starch (HAMSB) was protective. A group of twenty-three in iduals consumed 300 g/d of cooked red meat without (HRM diet) or with 40 g/d of HAMSB (HRM+HAMSB diet) over 4-week periods separated by a 4-week washout in a randomised cross-over design. Stool and rectal biopsy s les were collected for biochemical, microbial and immunohistochemical analyses at baseline and at the end of each 4-week intervention period. The HRM diet increased rectal O 6 MeG adducts relative to its baseline by 21 % ( P 0·01), whereas the addition of HAMSB to the HRM diet prevented this increase. Epithelial proliferation increased with both the HRM ( P 0·001) and HRM+HAMSB ( P 0·05) diets when compared with their respective baseline levels, but was lower following the HRM+HAMSB diet compared with the HRM diet ( P 0·05). Relative to its baseline, the HRM+HAMSB diet increased the excretion of SCFA by over 20 % ( P 0·05) and increased the absolute abundances of the Clostridium coccoides group ( P 0·05), the Clostridium leptum group ( P 0·05), Lactobacillus spp. ( P 0·01), Parabacteroides distasonis ( P 0·001) and Ruminococcus bromii ( P 0·05), but lowered Ruminococcus torques ( P 0·05) and the proportions of Ruminococcus gnavus , Ruminococcus torques and Escherichia coli ( P 0·01). HRM consumption could increase the risk of CRC through increased formation of colorectal epithelial O 6 MeG adducts. HAMSB consumption prevented red meat-induced adduct formation, which may be associated with increased stool SCFA levels and/or changes in the microbiota composition.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2018
Publisher: American Association for Cancer Research (AACR)
Date: 11-2011
DOI: 10.1158/1940-6207.CAPR-11-0176
Abstract: Population studies have shown that high red meat intake may increase colorectal cancer risk. Our aim was to examine the effect of different amounts and sources of dietary protein on induction of the promutagenic adduct O6-methyl-2-deoxyguanosine (O6MeG) in colonocytes, to relate these to markers of large bowel protein fermentation and ascertain whether increasing colonic carbohydrate fermentation modified these effects. Mice (n = 72) were fed 15% or 30% protein as casein or red meat or 30% protein with 10% high amylose maize starch as the source of resistant starch. Genetic damage in distal colonocytes was detected by immunohistochemical staining for O6MeG and apoptosis. Feces were collected for measurement of pH, ammonia, phenols, p-cresol, and short-chain fatty acids (SCFA). O6MeG and fecal p-cresol concentrations were significantly higher with red meat than with casein (P & 0.018), with adducts accumulating in cells at the crypt apex. DNA adducts (P & 0.01) and apoptosis (P & 0.001) were lower and protein fermentation products (fecal ammonia, P & 0.05 phenol, P & 0.0001) higher in mice fed resistant starch. Fecal SCFA levels were also higher in mice fed resistant starch (P & 0.0001). This is the first demonstration that high protein diets increase promutagenic adducts (O6MeG) in the colon and dietary protein type seems to be the critical factor. The delivery of fermentable carbohydrate to the colon (as resistant starch) seems to switch from fermentation of protein to that of carbohydrate and a reduction in adduct formation, supporting previous observations that dietary resistant starch opposes the mutagenic effects of dietary red meat. Cancer Prev Res 4(11) 1920–8. ©2011 AACR.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2022
DOI: 10.1200/JCO.2022.40.4_SUPPL.597
Abstract: 597 Background: Pancreatic adenocarcinoma patients have poor survival outcomes and there are no non-invasive tests to aid diagnosis or therapy. Detection of circulating tumour DNA (ctDNA) methylated for BCAT1 and/or IKZF1 is over 60% sensitive for colorectal adenocarcinoma. Both pancreatic and colorectal adenocarcinomas are of endodermal origin, therefore, these methylated biomarkers might also have utility in detecting pancreatic cancer. The aim of this study was to investigate whether in iduals with pancreatic adenocarcinoma have detectable methylated BCAT1 and IKZF1 DNA in circulation. Methods: In this pilot study, pre-treatment blood and clinicopathological findings were collected from 21 patients diagnosed with pancreatic adenocarcinoma. DNA isolated from plasma was bisulfite-converted and assayed for methylated BCAT1, IKZF1 and a non-methylated region in ACTB (for yield estimates). S les with methylation in either gene was deemed positive. Chi -squared test was used to compare positivity between Stage I/II and Stage III/IV cases. The sum of percent (%) methylation ([average BCAT1]+[average IKZF1])/average ACTB) ± standard error was compared between stages using Kruskal-Wallis rank test. Results: 10/21 (47.6%) patients were positive for methylated BCAT1 and/or IKZF1. There was a trend of increasing positivity with advancing stage (Stage I/II 2/8 (25.0%) vs Stage III/IV 8/13 (61.5%, p=0.104)), and for higher % methylation with more advanced disease (Stage II 0.01%±0.004 vs Stage IV 5.0%±3.7, p=0.06). No other comorbidities or demographics were associated with positivity. Conclusions: Assay for methylated BCAT1 and IKZF1 ctDNA detects approximately two-thirds of late-stage pancreatic adenocarcinoma. Future studies are warranted to assess the clinical utility of these biomarkers for detection and monitoring of pancreatic cancer. Clinical trial information: 12616001138471.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2014
DOI: 10.1158/1940-6207.CAPR-14-0053
Abstract: High red meat (HRM) intake is associated with increased colorectal cancer risk, while resistant starch is probably protective. Resistant starch fermentation produces butyrate, which can alter microRNA (miRNA) levels in colorectal cancer cells in vitro effects of red meat and resistant starch on miRNA expression in vivo were unknown. This study examined whether a HRM diet altered miRNA expression in rectal mucosa tissue of healthy volunteers, and if supplementation with butyrylated resistant starch (HRM+HAMSB) modified this response. In a randomized cross-over design, 23 volunteers undertook four 4-week dietary interventions an HRM diet (300 g/day lean red meat) and an HRM+HAMSB diet (HRM with 40 g/day butyrylated high amylose maize starch), preceded by an entry diet and separated by a washout. Fecal butyrate increased with the HRM+HAMSB diet. Levels of oncogenic mature miRNAs, including miR17–92 cluster miRNAs and miR21, increased in the rectal mucosa with the HRM diet, whereas the HRM+HAMSB diet restored miR17–92 miRNAs, but not miR21, to baseline levels. Elevated miR17–92 and miR21 in the HRM diet corresponded with increased cell proliferation, and a decrease in miR17–92 target gene transcript levels, including CDKN1A. The oncogenic miR17–92 cluster is differentially regulated by dietary factors that increase or decrease risk for colorectal cancer, and this may explain, at least in part, the respective risk profiles of HRM and resistant starch. These findings support increased resistant starch consumption as a means of reducing risk associated with an HRM diet. Cancer Prev Res 7(8) 786–95. ©2014 AACR.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NUTRES.2016.06.006
Abstract: O(6)-methyl guanine (O(6)MeG) adducts are major toxic, promutagenic, and procarcinogenic adducts involved in colorectal carcinogenesis. Resistant starch and its colonic metabolite butyrate are known to protect against oncogenesis in the colon. In this study, we hypothesized that a dietary intervention that specifically delivers butyrate to the large bowel (notably butyrylated high-amylose maize starch [HAMSB]) would reduce colonic levels of O(6)MeG in rats shortly after exposure to the deoxyribonucleic acid (DNA) alkylating agent azoxymethane (AOM) when compared with a low-amylose maize starch (LAMS). A further objective was to validate an immunohistochemistry (IHC) method for quantifying O(6)MeG against a high-performance liquid chromatography method using fluorescence and diode array detection. Rats were fed either LAMS or HAMSB diets for 4 weeks followed by a single injection of AOM or saline and killed 6 hours later. After AOM exposure, both IHC and high-performance liquid chromatography method using fluorescence and diode array detection measured a substantially increased quantity of DNA adducts in the colon (P<.001). Both techniques demonstrated equally that consumption of HAMSB provided a protective effect by reducing colonic adduct load compared with the LAMS diet (P<.05). In addition, IHC allowed visualization of the O(6)MeG distribution, where adduct load was reduced in the lower third of the crypt compartment in HAMSB-fed rats (P=.036). The apoptotic response to AOM was higher in the HAMSB-fed rats (P=.002). In conclusion, the reduction in O(6)MeG levels and enhancement of the apoptotic response to DNA damage in the colonic epithelium through consumption of HAMSB provide mechanistic insights into how HAMSB protects against colorectal tumorigenesis.
Publisher: Impact Journals, LLC
Date: 19-06-2018
Location: United States of America
No related grants have been discovered for Jean Winter.