Impact of Urbanization and Dietary Patterns on Development of Colorectal Cancer in Indian Population – A Review

Dear Editor: Cancer is a complex genetic disease which gradually progresses in relation to the downregulated expression of tumor suppressor genes (TSGs). Inactivation of TSGs has been known to contribute to the abnormal proliferation, transformation, and progression in human cancers. It has been widely demonstrated that both the genetic and epigenetic events, together, play a crucial role in tumor progression. Epigenetic is defined as the heritable changes in gene expression that are not caused by alterations in the DNA sequence. Several studies have demonstrated the epigenetic alterations in colorectal carcinoma. Colorectal cancer (CRC) is the third most common malignancy worldwide and a leading cause of cancer death in women and men in the USA. In contrast, the frequency of colorectal carcinoma is less in India. However, 20,159 cases of CRC among men and 16,317 cases among women were reported in India. The 14,134 and 11,556 mortality due to CRC was reported among men and women, respectively, in India. Most of the CRC cases originate from adenomas. The malignant potential of adenomas increases with size, grade of dysplasia, and degree of villous components, along with the number and order of genetic and epigenetic aberrations. Previous studies have also highlighted the hypermethylation in several TSGs in colorectal carcinoma. Recent reports suggest that PTEN has an important tumor suppressor role in colorectal carcinogenesis. However, more attentive study is needed to explore the association of PTEN loss with CRC development. PTEN, a tumor suppressor gene, has been recently isolated from chromosome 10q23.3. The involvement of PTEN promoter methylation has been reported in breast cancer, cervical cancer, endometrial cancer, colorectal cancer, and glioblastoma. However, no such study has been made to evaluate the role of the PTEN tumor suppressor gene in colorectal cancer in colorectal cancer in Indian population. The correlation of the progression of disease with that of the promoter hypermethylation seems to be an interesting phenomenon. Therefore, we aimed to analyze the PTEN gene promoter methylation in fresh colorectal cancer tissues and their adjacent normal tissues along with the colorectal metastases specimens and also to evaluate the association of PTEN hypermethylation with CRC progression. The major outcome of the study is that the PTEN hypermethylation is a frequent event in sporadic CRCs and colorectal metastases in the patients from Indian population. Promoter methylation of PTEN gene was determined by methylationspecific PCR. We also performed chi-square test to correlate the PTEN hypermethylation with the clinicobiological parameters of colorectal cancer and metastases specimens in order to evaluate the role of PTEN hypermethylation with the disease progression. Of the CRC specimens, 114 (51 %) have shown PTEN hypermethylation among the total of 223 CRC specimens. Thirty-eight specimens have been characterized as metastatic among 223 specimens. Thirty-one (82 %) specimens out of 38 colorectal metastases samples have also demonstrated PTEN hypermethylation. We would like to highlight the high rate of hypermethylation in advanced stage colorectal tumors than early stages of colorectal tumors. To examine the M. M. A. Rizvi (*) :A. Ali : S. J. Mehdi Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, Maulana Mohammad Ali Jauhar Marg, New Delhi 110025, India e-mail: rizvijmi@gmail.com

The human intestinal microbiota is a community of 1013-1014 microorganisms that reside in the intestine and normally participate in a symbiotic relationship with their eukaryotic host. The microbiome contains a wealth of information, encompassing 150 fold as many genes as the human genome. Recent studies have hinted that a core human microbiome exists at the gene level, with a large number of microbial genes and pathways shared among individuals. Deviations from this core microbiome could potentially affect human health and promote disease state. Thus characterizing the vast intestinal microbial community present in healthy as well as pathologic conditions will likely revolutionize our conception of bacteria/host interactions and identify new physiological processes influenced by the microbiota. Already the microbiota has been linked to cardiac development, angiogenesis, innate and adaptive immunity, metabolism, nutrient acquisition, and gastrointestinal development and homeostasis. Furthermore, alterations in the microbial community are associated with multiple diseases, including obesity, fatty liver disease, type 1 and type 2 diabetes, kidney disease, arthritis and inflammatory bowel diseases (IBD). Eukaryotes are equipped with an elegant repertoire of innate receptors each recognizing specific conserved microbial patterns present on various microorganisms, such as components of bacterial cell walls, locomotion system or nucleic acids. These microbial sensors are termed pattern recognition receptors (PRR) and include retinoic acid inducible gene-I like RNA helicases (RLH), C-type lectin receptors (CLR), Nucleotide-binding domain leucine-rich repeat proteins (NLR; also known as Nod-like receptors), and Toll-like receptors (TLR). Although the etiology of colitis-associated colorectal cancer remains elusive, innate host sensors have been shown to modulate the pathogenesis. Indeed, using mice exposed to the colon-specific carcinogen azoxymethane (AOM) compound and to the mucosal-damaging agent dextran sulfate sodium (DSS), numerous studies have revealed the differential contribution of innate sensors to CAC. For example, the NLR protein NOD1, a close relative of the IBD susceptible gene NOD2 protects against the development of colitis and colorectal cancer. Similarly, the adaptor protein MyD88 frequently utilized by TLR family members is protective in the context of AOM/DSS-induced colorectal cancer. Furthermore, the intracellular sensor NLRP3 also appears protective against colitis and CAC. In contrast, TLR4 signaling promotes the development of colorectal cancer in the AOM/DSS model. Although informative, these studies only capture the impact of various innate host responses on the development of colorectal cancer. The true impact of the microbiota could only be investigated using germ-free mice and gnotobiotic technology. To avoid the use of a chronic injury model (DSS), our laboratory has substituted the spontaneous IL-10−/− mouse model of intestinal inflammation for the AOM/DSS model. We have focused our attention on the role of microbial community on the development of colitis-associated colorectal cancer. Using this AOM/Il10−/− model of colorectal cancer in combination with gnotobiotic techniques, we observed a clear role for the microbiota in the development and progression of the pathology. Using metagenomic approaches, we observed a shift in bacterial community composition in mice bearing tumors compared to healthy controls. Interestingly, introduction of the probiotic VSL#3 changed microbial community structure and promoted the development of colorectal cancer in Il10−/− mice. Gnotobiotic experiments showed that bacteria-induced intestinal inflammation is not sufficient to promote colorectal cancer. Indeed, although the severity of colitis at the clinical and molecular levels is similar between Escherichia coli NC101 (E. coli) and Enterococcus faecalis (E. faecalis) monoassociated Il10−/− mice, tumor numbers were enhanced by more than 40 fold by the former commensal bacterium. We will present evidence that microbial composition and its associated genome/transcriptome plays a key role in the development of CAC. These findings would suggest that although chronic inflammation is a part of the pathology, microbial community and associated microbial genome is at the forefront of CAC susceptibility. Altering the composition of the microbiota may represent a novel means by which to modulate development of colorectal cancer in IBD patients. Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED06-04.

Speckle-Type Poz Protein (SPOP) involved in the regulation of proteasome-mediated degradation of several oncoproteins, resulting in cancer initiation and progression. Mutations in Adenomatous Polyposis Coli (APC) gene is reported in most sporadic and hereditary colorectal cancer (CRC). Identifying the cellular changes involved in carcinogenesis when APC is mutated is an important issue that needs attention. The tumor suppressive function of SPOP and APC has long been a major focus in the research field of colorectal cancer. However, the clinical significance of SPOP and APC gene alteration in CRC has not been established to date. Mutational analysis was performed by single-strand conformational polymorphism followed by Sanger sequencing, methylation status by methylation-specific PCR, and protein expression by immunohistochemistry on 142 tumor tissues along with their adjacent non-cancerous specimens. The overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier Curve. Mutation rates of APC and SPOP gene were 2.8% and 11.9% while that of promoter hypermethylation were 37% and 47%, respectively. The grade of differentiation and Lymph node metastasis were significantly correlated with APC methylation pattern (p ≤ 0.05). The down regulation of APC was more often seen in colonic cancer compared to rectal cancer (p = 0.07) and more commonly in T3-4 depth of invasion (p = 0.07) and in patients without lymphovascular and perineural invasion (p = 0.007, p = 0.08 respectively). The median overall survival and recurrence free survival (RFS) was 67 & 36months while 3-yr and 5-yr OS and RFS were 61.1% & 56.4% and 49.2% & 44.8%, respectively. APC promoter methylation had a better overall survival (p = 0.035) while loss of SPOP expression had a worse survival (p = 0.09). Our findings reveal high percentage of SPOP gene mutations in CRC. A significant link is found between promoter hyper methylationand protein expression in all mutant cases of APC and SPOP, suggesting that both genes may be associated in the development of colorectal cancer in people of Indian decent. Hypermethylation of APC gene and loss of SPOP expression have shown an association with disease prognosis and could be further studied looking at its potential role in planning adjuvant treatment in CRC patients.

ObjectiveColorectal cancer (CRC) development involves underlying modifications at genetic/epigenetic level. This study evaluated the role of Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation together/independently in sporadic CRC in Indian population and correlation with clinicopathological variables of the disease.MethodsOne hundred and twenty four consecutive surgically resected tissues (62 tumor and equal number of normal adjacent controls) of primary sporadic CRC were included and patient details including demographic characteristics, lifestyle/food or drinking habits, clinical and histopathological profiles were recorded. Polymerase chain reaction - Restriction fragment length polymorphism and direct sequencing for Kras gene mutation and Methylation Specific-PCR for RASSF1A, FHIT and MGMT genes was performed.ResultsKras gene mutation at codon 12 & 13 and methylated RASSF1A, FHIT and MGMT gene was observed in 47%, 19%, 47%, 37% and 47% cases, respectively. Alcohol intake and smoking were significantly associated with presence of Kras mutation (codon 12) and MGMT methylation (p-value <0.049). Tumor stage and metastasis correlated with presence of mutant Kras codon 12 (p-values 0.018, 0.044) and methylated RASSF1A (p-values 0.034, 0.044), FHIT (p-values 0.001, 0.047) and MGMT (p-values 0.018, 0.044) genes. Combinatorial effect of gene mutation/methylation was also observed (p-value <0.025). Overall, tumor stage 3, moderately differentiated tumors, presence of lymphatic invasion and absence of metastasis was more frequently observed in tumors with mutated Kras and/or methylated RASSF1A, FHIT and MGMT genes.ConclusionSynergistic interrelationship between these genes in sporadic CRC may be used as diagnostic/prognostic markers in assessing the overall pathological status of CRC.

Colorectal cancer (CRC) remains a major life-threatening malignancy, despite numerous therapeutic and screening attempts. Apoptosis and autophagy are two processes that share common signaling pathways, are linked by functional relationships and have similar protein components. During the development of cancer, the two processes can trigger simultaneously in the same cell, causing, in some cases, an inhibition of autophagy by apoptosis or apoptosis by autophagy. Malignant cells that have accumulated genetic alterations can take advantage of any alterations in the apoptotic process and as a result, progress easily in the cancerous transformation. Autophagy often plays a suppressive role during the initial stages of carcinogenicity, while in the later stages of cancer development it can play a promoting role. It is extremely important to determine the regulation of this duality of autophagy in the development of CRC and to identify the molecules involved, as well as the signals and the mechanisms behind it. All the reported experimental results indicate that, while the antagonistic effects of autophagy and apoptosis occur in an adverse environment characterized by deprivation of oxygen and nutrients, leading to the formation and development of CRC, the effects of promotion and collaboration usually involve an auxiliary role of autophagy compared to apoptosis. In this review, we elucidate the different roles of autophagy and apoptosis in human CRC development.

CA: A Cancer Journal for Clinicians publishes information about the prevention, early detection, and treatment of cancer, as well as nutrition, palliative care, survivorship, and additional topics of interest related to cancer care.

BackgroundAs a phosphorylated protein, NOLC1 is mainly located in the nucleus and is highly expressed in a variety of tumors, participating in the regulation of cell proliferation and aging. This study further investigated the role of NOLC1 in colorectal cancer tumors, aiming to provide sufficient scientific evidence for the clinical treatment of colorectal cancer.MethodsWe used TCGA, GEO, TNMplot, GEPIA, and other databases to explore the expression level of NOLC1 in colorectal cancer patients, as well as the correlation between the clinical characteristics of colorectal cancer patients and their expression, and conducted the prognostic analysis. Immunohistofluorescence (IHF) staining verified the analytical results. Subsequently, KEGG and GO enrichment analysis was used to identify the potential molecular mechanism of NOLC1 promoting the occurrence and development of colorectal cancer. The influence of NOLC1 expression on the immune microenvironment of colorectal cancer patients was further investigated using the TIMER database. GDSC database analysis was used to screen out possible anti-colorectal cancer drugs against NOLC1. Finally, we demonstrated the effect of NOLC1 on the activity and migration of colorectal cancer cells by Edu Cell proliferation assay and Wound Healing assay in vitro.ResultsOur results suggest that NOLC1 is overexpressed in colorectal cancer, and that overexpression of NOLC1 is associated with relevant clinical features. NOLC1, as an independent risk factor affecting the prognosis of colorectal cancer patients, can lead to a poor prognosis of colorectal cancer. In addition, NOLC1 may be associated with MCM10, HELLS, NOC3L, and other genes through participating in Wnt signaling pathways and jointly regulate the occurrence and development of colorectal cancer under the influence of the tumor microenvironment and many other influencing factors. Related to NOLC1: Selumetinib, Imatinib, and targeted drugs such as Lapatinib have potential value in the clinical application of colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells.ConclusionsHigh expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. Further studies and clinical trials are needed to confirm the role of NOLC1 in the development and progression of colorectal cancer.

Chronic inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying the development of colorectal cancers through chronic inflammation is not known. Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation in the immunoglobulin gene. We recently found that the mutagenic activity of AID expression links inflammation to the development of cancer. Aberrant AID expression is triggered by hepatitis C virus infection in human hepatocytes or Helicobacter pylori infection in human gastric epithelial cells, and leads to the generation of somatic mutations in various tumor-related genes. Here, we review our findings relating to how AID contributes to the development of colitis-associated colorectal cancers (CACs). Immunohistochemistry revealed the enhanced expression of endogenous AID protein in not only in the inflamed colonic mucosa of ulcerative colitis patients but also CAC tumor lesions. Pro-inflammatory cytokine TNF-α induced strong aberrant expression of AID via IκB kinase-dependent NF-κB-signaling pathways in human colonic epithelial cells. Furthermore, AID expression was also elicited in response to the T helper cell-2-driven cytokines IL-4 and IL-13, which are activated in human IBD. Aberrant activation of AID in colonic cells preferentially evoked genetic mutations in the TP53 gene, whereas there were no nucleotide alterations of the APC gene. These findings suggested that pro-inflammatory cytokine-mediated aberrant expression of AID in colonic epithelial cells plays a role as a genotoxic factor that enhances genetic instability during chronic colonic inflammation, leading to CAC development.

Relevance.Nutrition is the most important biological factor on which the functioning of the human body depends. The link between the development of colorectal cancer and nutrition and eating habits is well known: excessive consumption of red meat, fats, alcohol, lack of dietary fiber, obesity. Objective: To assess the prevalence and significance of factors related to nutrition and food habits in the development of colorectal cancer (CRC) in the population of the Omsk region.Materials and methods.An epidemiological analytical study (case-control) was conducted, in which 609 people took part - residents of the Omsk Region aged 30 to 85 years (average age 51.2 years; 95% CI 48.1 – 54.3). The study examined 23 factors characterizing the diet and eating habits of study participants.Result and discussion.Of the 23 risk factors for CRC associated with nutrition and food habits, only six confirmed their importance to the residents of the Omsk region: a body mass index of more than 25, alcohol consumption more than twice a month with a predominance of strong, the frequency of red meat consumed more than 10 times a month, the amount of fresh fruit consumed is less than 100 grams at a time, the preference for fatty foods.Findings.The implementation of preventive measures, taking into account the prevalence of risk factors for CRC, including factors related to nutrition and eating habits, reduces the population and individual risk of this pathology in the population of the region, as well as health losses due to malignant neoplasms of the colon and colon.

Colorectal cancer (CRC) is one of the most common cancers worldwide. The occurrence and development of CRC are related to multiple risk factors such as gut microbiota. Indeed, gut microbiota plays an important role in the different phases of colorectal cancers (CRCs) from oncogenesis to metastasis. Some specific bacteria such as Fusobacterium nucleatum (F. nucleatum) associated with CRCs have been found. However, recently identified bile acid and tryptophan metabolites as well as short chain fatty acids (SCFAs), which are derived from gut microbiota, can also exert effects on the CRCs such as that SCFAs directly inhibit CRC growth. Importantly these metabolites also modulate immune responses to affect CRCs. They not only act as tumor inhibiting factor(s) but also promotor(s) in the occurrence, development, and metastasis of CRCs. While gut microbiota metabolites (GMMs) inhibit immunity against CRCs, some of them also improve immune responses to CRCs. Notably, GMMs also potentially affect the shaping of immune-privileged metastatic niches through direct roles or immune cells such as macrophages and myeloid-derived suppressive cells. These findings offer new insights for clinical application of gut microbiota in precise and personalized treatments of CRCs. Here, we will mainly discuss direct and indirect (via immune cells) effects of GMMs, especially SCFAs, bile acid and tryptophan metabolites on the occurrence, development and metastasis of CRCs.

NG03: Marine omega-3 polyunsaturated fatty acid and colorectal cancer prevention and treatment

Background: Selenium manifests its biological effects through its incorporation into selenoproteins, which play several roles in countering oxidative and inflammatory responses implicated in colorectal carcinogenesis. Selenoprotein genetic variants may contribute to colorectal cancer (CRC) development, as we previously observed for SNP variants in a large European prospective study and a Czech case–control cohort. Methods: We tested if significantly associated selenoprotein gene SNPs from these studies were also associated with CRC risk in case–control studies from Ireland (colorectal neoplasia, i.e., cancer and adenoma cases: 450, controls: 461) and the Czech Republic (CRC cases: 718, controls: 646). Genotyping of 23 SNPs (20 in the Irish and 13 in the Czechs) was performed by competitive specific allele-specific PCR (KASPar). Multivariable adjusted logistic regression was used to assess the associations with CRC development. Results: We found significant associations with an increased CRC risk for rs5859 (SELENOF) and rs2972994 (SELENOP) in the Irish cohort but only with rs4802034 (SELENOV) in the Czechs. Significant associations were observed for rs5859 (SELENOF), rs4659382 (SELENON), rs2972994 (SELENOP), rs34713741 (SELENOS), and the related Se metabolism gene variant rs2275129 (SEPHS1) with advanced colorectal neoplasia development. However, none of these findings retained significance after multiple testing corrections. Conclusions: Several SNPs previously associated with CRC risk were also associated with CRC or colorectal neoplasia development in either the Irish or Czech cohorts. Selenoprotein gene variation may modify CRC risk across diverse European populations, although the specific variants may differ.

IntroductionHigher intake levels of dietary calcium have been shown to be associated with decreased risk of colorectal cancer (CRC) development in several prospective studies. However, very little information is available on the CRC risk association of circulating calcium concentrations, particularly since elevated serum calcium has been associated in some settings with metabolic dysfunction and diabetes, factors which appear to be related to higher CRC risk.Material and methodsIn order to explore this question, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between serum calcium levels and the risk of colorectal cancer (CRC) development. 975 first incident CRC cases were matched to 975 matched controls from within the cohort by sex, age, study centre, length of follow-up and some additional relevant variables. Serum calcium levels were measured using reflection X-ray fluorescence spectrometry on the pre-diagnostically-collected serum samples from cases and matched controls.Conditional logistic regression was used to calculate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CIs).Results and discussionsHigher levels of serum calcium were associated with reduced risk of CRC (OR Q5vs.Q1=0.69, 95% CI: 0.48–0.99; p trend=0.02). Sub-group analyses by anatomical sub-site suggest that the observed inverse cancer risk association is apparent in the colon (OR Q5vs.Q1=0.61, 95% CI: 0.38–0.98; p trend=0.04) and not in the rectum (OR Q5vs.Q1=0.99, 95% CI: 0.53–1.85; p trend=0.54) where the association appeared to be non-linear. The magnitude of the association in the colon is similar to that observed with dietary calcium at the same anatomical site. Stratified analysis by sex is suggestive of a stronger association for men than women.ConclusionIn conclusion, elevated serum calcium levels are inversely associated with risk of CRC development, with some evidence for heterogeneity by anatomical sub-site and sex. Additional studies are necessary to confirm these findings and to further investigate potential underlying mechanisms for the role of serum calcium in CRC development.

BackgroundRecent research has identified a potential protective effect of higher numbers of circulating lymphocytes on colorectal cancer (CRC) development. However, the importance of different lymphocyte subtypes and activation states in CRC development and the biological pathways driving this relationship remain poorly understood and warrant further investigation. Specifically, CD4+ T cells – a highly dynamic lymphocyte subtype – undergo remodelling upon activation to induce the expression of genes critical for their effector function. Previous studies investigating their role in CRC risk have used bulk tissue, limiting our current understanding of the role of these cells to static, non-dynamic relationships only.MethodsHere, we combined two genetic epidemiological methods – Mendelian randomisation (MR) and genetic colocalisation – to evaluate evidence for causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation stage. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across five CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). We repeated analyses stratified by CRC anatomical subsites and sex, and performed a sensitivity analysis to evaluate whether the observed effect estimates were likely to be CD4+ T cell-specific.ResultsWe identified six genes with evidence (FDR-P<0.05 in MR analyses and H4>0.8 in genetic colocalisation analyses) for a causal role of CD4+ T cell expression in CRC development – FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258. We observed differences in causal estimates of gene expression on CRC risk across different CD4+ T cell subtypes and activation timepoints, as well as CRC anatomical subsites and sex. However, our sensitivity analysis revealed that the genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes.ConclusionsOur study demonstrates the importance of capturing the dynamic nature of CD4+ T cells in understanding disease risk, and prioritises genes for further investigation in cancer prevention research.

Colorectal cancer is a significant public health concern. As a multistage and multifactorial disease, environmental and genetic factors interact at each stage of the process, and an individual's lifestyle also plays a relevant role. We set out to review the scientific evidence to study the need to investigate the role of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) gene as a biomarker of the physical activity's (PA) effect on colorectal cancer. PA is a protective factor against colorectal cancer and usually increases the expression of PGC-1α This gene has pleiotropic roles and is the main regulator of mitochondrial functions. The development of colorectal cancer has been associated with mitochondrial dysfunction; in addition, alterations in this organelle are associated with colorectal cancer risk factors, such as obesity, decreased muscle mass, and the aging process. These are affected by PA acting, among other aspects, on insulin sensitivity and oxygen reactive species/redox balance. Therefore, this gene demands special attention in the understanding of its operation in the consensual protective effect of PA in colorectal cancer. A significant amount of indirect evidence points to PGC-1α as a potential biomarker in the PA-protective effect on colorectal cancer. The article focuses on the possible involvement of PGC-1α in the protective role that physical activity has on colorectal cancer. This is an important topic both in relation to advances in prevention of the development of this widespread disease and in its therapeutic treatment. We hope to generate an initial hypothesis for future studies associated with physical activity-related mechanisms that may be involved in the development or prevention of colorectal cancer. PGC-1α is highlighted because it is the main regulator of mitochondrial functions. This organelle, on one hand, is positively stimulated by physical activity; on the other hand, its dysfunction or reduction increases the probability of developing colorectal cancer. Therefore, we consider the compilation of existing information about the possible ways to understand the mechanisms of this gene to be highly relevant. This study is based on evidence of PGC-1α and physical activity, on PGC-1α and colorectal cancer, on colorectal cancer and physical activity/inactivity, and the absence of studies that have sought to relate all of these variables. Cancer Prev Res; 11(9); 523-34. ©2018 AACR.