[show abstract][hide abstract] ABSTRACT: Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key ‘stemness’ property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term
and irreversible impairment of tumor growth. Targeting the BMI-1–related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.
[show abstract][hide abstract] ABSTRACT: Cancer stem cells are thought to be resistant to anticancer therapies and are able to repopulate tumors and sustain tumor growth. The authors establish BMI-1 as a crucial regulator of cancer cell stemness in colorectal tumors and develop a chemical inhibitor that targets cancer stem cell renewal by reducing the levels of BMI-1. This strategy affords antitumor effects in vitro and in vivo and may pave the way for the precise targeting of elusive cancer stem cells.
Nature medicine 12/2013; 19(12). · 27.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level. Methods: Using GWAS genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by employing the likelihood ratio test (LRT) nested in logistic regression models and Ingenuity Pathway Analysis (IPA). Results: After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P=3.29×10^(-6)) and a near significant interaction of calcium signaling pathway with diabetes (P=1.57×10^(-4)) in modifying the risk of pancreatic cancer was observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1 and GNAS. None of the individual genes or SNPs except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91×10^(-7)) at a false discovery rate of 6%. Conclusions: Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets. Impact: Gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.
Cancer Epidemiology Biomarkers & Prevention 10/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways. Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for over 600 tagSNPs and 99 SNPs were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls). Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (odds ratio per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the "effective" number of markers in Stage 2 (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, BMI levels, regular aspirin use or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822. Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk. Impact: Further replication in independent samples is warranted.
Cancer Epidemiology Biomarkers & Prevention 09/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Experimental evidence has demonstrated an anti-neoplastic role for vitamin D in the colon and higher circulating 25-hydroxyvitamin D (25[OH]D) levels are consistently associated with a lower risk of colorectal cancer (CRC). Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified SNPs from four gene regions, collectively explain approximately 5% of the variance in circulating 25(OH)D. Methods: We investigated whether six polymorphisms in GC, CYP2R1, CYP24A1 and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with CRC risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We performed a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS). Results: We did not observe a statistically significant association between the 25(OH)D associated SNPs and CRC marginally, conditionally, or as a GRS, or for colon or rectal cancer separately or combined. Conclusions: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of CRC. Additional work is warranted to investigate the complex relationship between 25(OH)D and CRC risk. Impact: There was no association observed between genetic markers of circulating 25(OH)D and CRC. These genetic markers account for a small proportion of the variance in 25(OH)D.
Cancer Epidemiology Biomarkers & Prevention 08/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are many factors to consider in managing patients with multiple polyps. Familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, and the hamartomatous and hyperplastic polyposis syndromes should be considered in the differential diagnosis. Family history helps determine which genetic tests to offer in confirming a diagnosis. A genetic diagnosis allows relatives to undergo predictive testing and helps to streamline surgical and screening recommendations for patients and their relatives. Knowledge about etiology, natural history, and genetics of the polyposis syndromes has guided clinical management recommendations for these patients. Nevertheless, it is important to recognize that most patients with multiple adenomatous or hyperplastic polyps do not have a known genetic condition.
[show abstract][hide abstract] ABSTRACT: Among patients with initially unresectable colorectal cancer liver metastases (CLM), a subset are rendered resectable following the administration of systemic chemotherapy. This study reports the results achieved in liver resections performed at a single hepatobiliary referral centre after downsizing chemotherapy in patients with initially unresectable CLM.
All liver resections for CLM performed over a 10-year period at the Toronto General Hospital were considered. Data on initially non-resectable patients who received systemic therapy and later underwent surgery were included for analysis.
Between January 2002 and July 2012, 754 liver resections for CLM were performed. A total of 24 patients were found to meet the study inclusion criteria. Bilobar CLM were present in 23 of these 24 patients. The median number of tumours was seven (range: 2-15) and median tumour size was 7.0 cm (range: 1.0-12.8 cm) before systemic therapy. All patients received oxaliplatin- or irinotecan-based chemotherapy. Fourteen patients received combined treatment with bevacizumab. Negative margin (R0) resection was accomplished in 21 of 24 patients. There was no perioperative mortality. Ten patients suffered perioperative morbidity. Eighteen patients suffered recurrence of disease within 9 months. Rates of disease-free survival at 1, 2 and 3 years were 47.6% [95% confidence interval (CI) 30.4-74.6%], 23.8% (95% CI 11.1-51.2%) and 19.0% (95% CI 7.9-46.0%), respectively. Overall survival at 1, 2 and 3 years was 91.5% (95% CI 80.8-100%), 65.3% (95% CI 48.5-88.0%) and 55.2% (95% CI 37.7-80.7%), respectively.
Liver resection in initially unresectable CLM can be performed with low rates of morbidity and mortality in patients who respond to systemic chemotherapy, although these patients do experience a high frequency of disease recurrence.
[show abstract][hide abstract] ABSTRACT: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer.
We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations.
Two correlated SNPs-rs10090154 and rs4242382-in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites.
This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.
[show abstract][hide abstract] ABSTRACT: Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability.
We assessed the differences in survival by colon or rectal cancer site, considering the contribution of microsatellite instability to such differences.
This is a population-based prospective cohort study for cancer survival.
This study was conducted within the Colon Cancer Family Registry, an international consortium. Participants were identified from population-based cancer registries in the United States, Canada, and Australia.
Information on tumor site, microsatellite instability, and survival after diagnosis was available for 3284 men and women diagnosed with incident invasive colon or rectal cancer between 1997 and 2002, with ages at diagnosis ranging from 18 to 74.
Cox regression was used to calculate hazard ratios for the association between all-cause mortality and tumor location, overall and by microsatellite instability status.
Distal colon (HR, 0.59; 95% CI, 0.49-0.71) and rectal cancers (HR, 0.68; 95% CI, 0.57-0.81) were associated with lower mortality than proximal colon cancer overall. Compared specifically with patients with proximal colon cancer exhibiting no/low microsatellite instability, patients with distal colon and rectal cancers experienced lower mortality, regardless of microsatellite instability status; patients with proximal colon cancer exhibiting high microsatellite instability had the lowest mortality.
Study limitations include the absence of stage at diagnosis and cause-of-death information for all but a subset of study participants. Some patient groups defined jointly by tumor site and microsatellite instability status are subject to small numbers.
Proximal colon cancer survival differs from survival for distal colon and rectal cancer in a manner apparently dependent on microsatellite instability status. These findings support the premise that proximal colon, distal colon, and rectal cancers are clinicopathologically distinct.
Diseases of the Colon & Rectum 08/2013; 56(8):937-944. · 3.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long non-coding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrated that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation on the SNP-conferred cancer risk.
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: An aberrant right hepatic artery (aRHA) may pose technical and oncologic challenges during pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) as a result of its proximity to the head of the pancreas. The aim of this study was to assess the impact of an aRHA on resectability, and perioperative and oncologic outcomes after PD for PA. METHODS: An 11-year retrospective cohort study was conducted. A total of 289 patients with PA scheduled for PD with intent for resection were included in the study. RESULTS: Of 289 patients, 249 underwent PD and 40 were found to have unresectable tumours. Incidences of aRHA in the resectable (14.9%) and unresectable (7.5%) groups were similar (P = 0.2); the main reasons for aborting PD were not directly related to the presence of an aRHA. In patients who underwent resection, complications occurred more frequently in the standard PD group (41.5% versus 24.3%; P = 0.04), but there was no difference in rates of positive margin (R1) resection (10.8% versus 16.0%; P = 0.4) or median overall survival (17 months versus 23 months; P = 0.1) between patients with and without an aRHA. CONCLUSIONS: The presence of an aRHA in patients with PA does not affect resectability. In patients with resectable tumours, the presence of an aRHA does not increase morbidity or R1 resection rates and does not impact on overall survival.
[show abstract][hide abstract] ABSTRACT: To investigate the survival of individuals with colorectal cancer (CRC) with inflammatory bowel disease (IBD-associated CRC) compared to that of individuals without IBD diagnosed with CRC.
Epidemiologic, clinical, and follow-up data were obtained from the Colon Cancer Family Registry (Colon CFR). IBD-associated cases were identified from self-report of physician diagnosis. For a subset of participants, medical records were examined to confirm self-report of IBD. Cox proportional hazards regression was applied to estimate adjusted hazard ratios (aHR) and 95%CI of mortality, comparing IBD-associated to non-IBD-associated CRC, adjusted for age at CRC diagnosis, sex, Colon CFR phase, and number of prior endoscopies. Following imputation to complete CRC stage information, adjustment for CRC stage was examined.
A total of 7202 CRC cases, including 250 cases of IBD-associated CRC, were analyzed. Over a twelve year follow-up period following CRC diagnosis, 2013 and 74 deaths occurred among non-IBD associated CRC and IBD-associated CRC patients, respectively. The difference in survival between IBD-associated and non-IBD CRC cases was not statistically significant (aHR = 1.08; 95%CI: 0.85-1.36). However, the assumption of proportional hazards necessary for valid inference from Cox regression was not met over the entire follow-up period, and we therefore limited analyses to within five years after CRC diagnosis when the assumption of proportional hazards was met. Over this period, there was evidence of worse prognosis for IBD-associated CRC (aHR = 1.36; 95%CI: 1.05-1.76). Results were similar when adjusted for CRC stage, or restricted to IBD confirmed in medical records.
These results support the hypothesis that IBD-associated CRC has a worse prognosis than non-IBD-associated CRC.
World Journal of Gastroenterology 06/2013; 19(21):3241-8. · 2.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. METHODS: We completed exome sequencing on 40 affected cases from 16 multi-case pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single nucleotide variants (SNVs) predicted to be benign. RESULTS: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or non-coding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. CONCLUSIONS: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in colorectal cancer susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.
Cancer Epidemiology Biomarkers & Prevention 05/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing.
[show abstract][hide abstract] ABSTRACT: Colorectal cancer (CRC) continues to rank as the third most common cancer in Western society and the second leading cause of cancer death in North America. There are at least three distinct, and relatively discreet, molecular pathways associated with this disease: chromosomal instability (CIN), microsatellite instability (MSI) and the cytosine polyguanine island methylator phenotype. Defects in the DNA mismatch repair system (MMR) account for the MSI phenotype and genotype of about 15 % of CRC. Although high frequency MSI tumors have better stage independent prognosis compared to those with CIN, MMR deficient CRC appears to be resistant to fluorouracil based treatment, but sensitive to other therapeutic regimens. This review summarises current literature on differential chemosensitivity of MMR-deficient CRC.
[show abstract][hide abstract] ABSTRACT: Introduction: The HOXB13 pGly84Glu mutation has recently been associated with an increased risk of prostate cancer but the association of other cancer sites with this allele has not been assessed. Data has suggested that HOXB13 expression levels are decreased in colorectal cancer (CRC) cell lines indicating this gene may be involved in colorectal tumourigenesis. Methods: To evaluate a potential association of this mutation with CRC, we genotyped the mutation in 2695 CRC cases and 4593 controls from population-based registries in Canada and Australia. Results: The HOXB13 pGly84Glu mutation was more common in CRC cases than controls (0.48% vs. 0.17%, P=0.02) indicating a significant association between the HOXB13 variant and CRC risk (OR=2.8; 95%CI: 1.2-6.8). This association was attenuated but remained significant with the inclusion of previously published and publicly available genotype data. Pedigree analysis of cases and controls revealed that 7/21 HOXB13 mutation carriers had a family history of prostate cancer. Discussion: This report is the first to suggest a risk of CRC associated with mutations in the HOXB13 gene. These findings require further validation but may be of importance in the screening and genetic counseling of families known to carry the HOXB13 pGly84Glu mutation.