Epigenetic Influences in the Obesity/Colorectal Cancer Axis: A Novel Theragnostic Avenue

The World Health Organization (WHO) considers that obesity has reached proportions of pandemic. Experts also insist on the importance of considering obesity as a chronic disease and one of the main contributors to the worldwide burden of other nontransmissible chronic diseases, which have a great impact on health, lifestyle, and economic cost. One of the most current challenges of biomedical science faces is to understand the origin of the chronic nontransmissible diseases, such as obesity and cancer. There is a large evidence, both in epidemiological studies in humans and in animal models, of the association between obesity and an increased risk of cancer incidence. In the last years, the initial discovery of epigenetic mechanisms represents the most relevant finding to explain how the genome interacts with environmental factors and the ripple effects on disease pathogeneses. Since then, all epigenetic process has been investigated by the scientific communities for nearly two decades to determine which components are involved in this process. DNA/RNA methylation and miRNA are classified as two of the most important representative classes of such epigenetic mechanisms and dysregulated activity of such mechanism can certainly contribute to disease pathogenesis and/or progression especially in tumors. This review article serves to highlight the impact of DNA/RNA methylation and miRNA-based epigenetic mechanism activities in the interplay between obesity and the development and clinical significance of colorectal cancer.

Download Full-text

A Meta-Analysis of Obesity and Risk of Colorectal Cancer in Patients with Lynch Syndrome: The Impact of Sex and Genetics

Nutrients ◽

10.3390/nu13051736 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1736

Author(s):

Matteo Lazzeroni ◽

Federica Bellerba ◽

Mariarosaria Calvello ◽

Finlay Macrae ◽

Aung Ko Win ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Publication Bias ◽

Colorectal Neoplasia ◽

Meta Analysis ◽

Random Effect ◽

Normal Weight ◽

Increased Risk ◽

Risk Of Cancer ◽

The Impact

There appears to be a sex-specific association between obesity and colorectal neoplasia in patients with Lynch Syndrome (LS). We meta-analyzed studies reporting on obesity and colorectal cancer (CRC) risk in LS patients to test whether obese subjects were at increased risk of cancer compared to those of normal weight. We explored also a possible sex-specific relationship between adiposity and CRC risk among patients with LS. The summary relative risk (SRR) and 95% confidence intervals (CI) were calculated through random effect models. We investigated the causes of between-study heterogeneity and assessed the presence of publication bias. We were able to retrieve suitable data from four independent studies. We found a twofold risk of CRC in obese men compared to nonobese men (SRR = 2.09; 95%CI: 1.23–3.55, I2 = 33%), and no indication of publication bias (p = 0.13). No significantly increased risk due to obesity was found for women. A 49% increased CRC risk for obesity was found for subjects with an MLH1 mutation (SRR = 1.49; 95%CI: 1.11–1.99, I2 = 0%). These results confirm the different effects of sex on obesity and CRC risk and also support the public measures to reduce overweight in people with LS, particularly for men.

Download Full-text

Clinicopathological features of Egyptian colorectal cancer patients regarding somatic genetic mutations especially in KRAS gene and microsatellite instability status: a pilot study

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-019-0028-z ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Neemat M. Kassem ◽

Gamal Emera ◽

Hebatallah A. Kassem ◽

Nashwa Medhat ◽

Basant Nagdy ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Human Cancer ◽

Statistical Significance ◽

Public Health Problem ◽

World Health ◽

Cpg Island Methylator Phenotype ◽

Number Of Patients ◽

The Impact

Abstract Background Colorectal cancer (CRC) is the third most common cause of cancer-related deaths which contributes to a significant public health problem worldwide with 1.8 million new cases and almost 861,000 deaths in 2018 according to the World Health Organization. It exhibits 7.4% of all diagnosed cancer cases in the region of the Middle East and North Africa. Molecular changes that happen in CRCs are chromosomal instability, microsatellite instability (MSI), and CpG island methylator phenotype. The human RAS family (KRAS, NRAS, and HRAS) is the most frequently mutated oncogenes in human cancer appearing in 45% of colon cancers. Determining MSI status across CRCs offers the opportunity to identify patients who are likely to respond to targeted therapies such as anti-PD-1. Therefore, a method to efficiently determine MSI status for every cancer patient is needed. Results KRAS mutations were detected in 31.6% of CRC patients, namely in older patients (p = 0.003). Codons 12 and 13 constituted 5/6 (83.3%) and 1/6 (16.7%) of all KRAS mutations, respectively. We found three mutations G12D, G12C, and G13D which occur as a result of substitution at c.35G>A, c.34G>T, and c.38G>A and have been detected in 4/6 (66.6%), 1/6 (16.7%), and 1/6 (16.7%) patients, respectively. Eleven (57.9%) patients had microsatellite instability-high (MSI-H) CRC. A higher percentage of MSI-H CRC was detected in female patients (p = 0.048). Eight patients had both MSI-H CRC and wild KRAS mutation with no statistical significance was found between MSI status and KRAS mutation in these studied patients. Conclusion In conclusion, considering that KRAS mutations confer resistance to EGFR inhibitors, patients who have CRC with KRAS mutation could receive more tailored management by defining MSI status. MSI-high patients have enhanced responsiveness to anti-PD-1 therapies. Thus, the question arises as to whether it is worth investigating this association in the routine clinical setting or not. Further studies with a larger number of patients are needed to assess the impact of MSI status on Egyptian CRC care.

Download Full-text

Management of colorectal cancer in the era of COVID-19: Challenges and suggestions

Science Progress ◽

10.1177/00368504211010626 ◽

2021 ◽

Vol 104 (2) ◽

pp. 003685042110106

Author(s):

Walid Alam ◽

Youssef Bouferraa ◽

Yolla Haibe ◽

Deborah Mukherji ◽

Ali Shamseddine

Keyword(s):

Colorectal Cancer ◽

Treatment Protocols ◽

Cancer Management ◽

Increased Risk ◽

Huge Impact ◽

Treatment Plans ◽

Virus Exposure ◽

Risk Of Exposure ◽

Colorectal Cancer Patients ◽

The Impact

The Coronavirus (COVID-19) pandemic had a huge impact on all sectors around the world. In particular, the healthcare system has been subject to an enormous pressure that has surpassed its ability in many instances. Additionally, the pandemic has called for a review of our daily medical practices, including our approach to colorectal cancer management where treatment puts patients at high risk of virus exposure. Given their higher median age, patients are at an increased risk for severe symptoms and complications in cases of infection, especially in the setting of immunosuppression. Therefore, a review of the routine colorectal cancer practices is needed to minimize risk of exposure. Oncologists should weigh risk of exposure versus the patient’s oncologic benefits when approaching management. In addition, treatment protocols should be modified to minimize hospital visits and admissions while maintaining the same treatment efficacy. In this review, we will focus on challenges that colorectal cancer patients face during the pandemic, while highlighting the priority in each case. We will also discuss the evidence for potential modifications to existing treatment plans that could reduce infectious exposure without compromising care. Finally, we will discuss the impact of the socio-economic difficulties faced by Lebanese patients due to a poor economy toppled by an unexpected pandemic.

Download Full-text

CANCER OF THE ORGANS OF THE REPRODUCTIVE SYSTEM IN WOMEN WITH TYPE 2 DIABETES. EFFECTS OF ANTIDIABETIC THERAPY

Wiadomości Lekarskie ◽

10.36740/wlek202005124 ◽

2020 ◽

Vol 73 (5) ◽

pp. 967-971

Author(s):

Tamara S. Vatseba

Keyword(s):

Type 2 Diabetes ◽

Combination Therapy ◽

Postmenopausal Women ◽

Reproductive System ◽

Uterine Cancer ◽

Antidiabetic Therapy ◽

Increased Risk ◽

Risk Of Cancer ◽

The Impact

The aim: to investigate the prevalence of cancer of the reproductive system in women with type 2 diabetes, and to examine the impact of antidiabetic therapy on cancer risk of this localization. Materials and methods: The study included a retrospective analysis of medical records of women with T2D with first diagnosed cancer during 2012-2016. The bases for the study were specialized medical institutions in Ivano-Frankivsk region. The obtained results were processed using statistical programs “Microsoft Excel” and “Statistika-12”. Results: Breast, uterine, and ovarian cancer were detected in 202 postmenopausal women, 63.92% from the total number of cancer cases in women. An increased risk of breast [OR = 1.24; 95% CI (1.04 – 1.50) P = 0.019] and uterine cancer [OR = 1.32; 95% CI (1.02 – 1.69) P = 0.040] has been identified. Most often, before the detection of cancer, women received combination therapy with sulfonylurea and metformin (83 patients (57.64%)) with BMI 32.64 ± 3.69 kg/m2. The difference between risk of cancer on metformin monotherapy and on sulfonylurea monotherapy [OR = 2.17; 95% CI (0.88 – 5.36) P = 0.141] or on combination therapy [OR = 1.68; 95% CI (0.76 – 3.74) P = 0.276] was not found. Conclusions: Postmenopausal women have an increased risk of breast and uterine cancer and are recommended to be screened for these diseases

Download Full-text

Genetic variants involved in the lipid metabolism pathway to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.118 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 118-118

Author(s):

Jingyuan Wang ◽

Joshua Millstein ◽

Fotios Loupakis ◽

Sebastian Stintzing ◽

Hiroyuki Arai ◽

...

Keyword(s):

Colorectal Cancer ◽

Lipid Metabolism ◽

Genetic Variants ◽

Progression Free Survival ◽

Snp Markers ◽

Acid Oxidation ◽

Metabolism Pathway ◽

Increased Risk ◽

In Fire ◽

The Impact

118 Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches the glucose-dependent metabolism to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer. Previous reports suggested that polymorphisms of the lipid metabolism-related genes are associated with the increased risk of CRC and poor clinical outcome in CRC. Therefore, we hypothesized that genetic variants in the lipid metabolism pathway may predict first-line treatment outcome in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, FIRE-3 and MAVERICC, was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 25 selected SNPs in 10 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1, LPCAT2, PPARG, CPT1A, ACSS2, SREBF1, FASN, ACACA) was analyzed. Those treated with FOLFIRI/ bevacizumab (bev) in FIRE-3 (n = 107) and MAVERICC (n = 163) served as discovery and validation cohorts respectively, while FIRE-3 FOLFIRI/ cetuximab (cet) (n = 129) arm was used as the control. Interaction between each SNP and treatment was evaluated in FIRE-3 (FOLFIRI/bev arm vs. FOLFIRI/cet arm). Results: In the discovery (FIRE-3 bev) cohort, pts with FASN rs4485435 any C allele (N = 21) showed significantly shorter progression-free survival (PFS) (8.69 vs 13.48 months) compared to carriers of G/G (N = 62) in both univariate (hazard ratio [HR] = 2.88; 95% confidence interval [CI]: 1.57-5.29; p = 0.00037) and multivariate (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analyses. These data were validated in the MAVERICC bev cohort in multivariate analysis (11.17 vs 14.06 months; HR = 2.07; 95%CI: 1.15-3.74; p = 0.02). Pts carrying any T allele in PPARG rs3856806 (N = 36) showed significantly longer overall survival (OS) (Not reached vs 42 months) than carriers of C/C (n = 93) in the FIRE-3 cet cohort in both univariate (HR = 0.4; 95%CI 0.17-0.92; p = 0.03) and multivariate (HR = 0.37; 95%CI 0.15-0.93; p = 0.02) analyses, but the association was not observed in the bev cohort of MAVERICC and FIRE-3. In the comparison of bev arm vs cet arm in FIRE-3, interactions were shown with FASN rs4485435 (p = 0.017) on PFS and PPARG rs3856806 (p = 0.059) on OS. Conclusions: Our study demonstrates for the first time that FASN polymorphism could predict outcomes of bev-based treatment in mCRC patients; Meanwhile PPARG polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF/EGFR treatment.

Download Full-text

Impact assessment of the TFA regulation on fatty acid composition of foods in Hungary

European Journal of Public Health ◽

10.1093/eurpub/ckaa165.363 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

A Varga ◽

E Sarkadi Nagy ◽

L Zámbó ◽

É Illés ◽

M Bakacs ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Trans Fatty Acids ◽

Saturated Fat ◽

Portion Size ◽

World Health ◽

Food Sources ◽

Increased Risk ◽

Total Fat ◽

The Impact

Abstract Trans fatty acids are formed during the industrial processing of food, and are proven to be harmful for the human body. They have been associated with increased risk of cardiovascular disease, abdominal obesity, diabetes, and certain types of cancer. Decree 71/2013. (XI. 20.) of the Ministry of Human Capacities, which has been in force since 2014, defines the highest permitted amount of trans fats in food products placed on the market in Hungary. The impact of the decree on the industrially produced trans fatty acids (iTFA) availability and population intake was assessed in 2017. Results demonstrated that iTFA were replaced by other fatty acids due to the legislation. In 2019, we investigated food groups which had high measured TFA content before the regulation entered into force and compared the total fat and fatty acid profiles to the same brand or similar products being on the market afterwards. In collaboration with the World Health Organization, this was the first assessment to determine to which extent manufacturers increased saturated fat (SFA) content of foodstuffs to reduce iTFA content. In those product groups, which were identified as significant food sources of iTFA before introducing the regulation (biscuits, coffee creamers and flavorings, sweets, bakery products, confectionary, wafers, margarines) we found no significant changes in the total fat content, while in most foodstuffs the average proportion of SFA was higher after reformulation, as iTFA were mainly substituted with SFA in 61% of the products, with cis-MUFA in 25% and cis-PUFA in 14% of the products, respectively. Evidence from this analysis supports concerns that eliminating iTFA in certain foodstuffs leads to unwanted substitution with saturated fat, hence reducing the possible health benefits. Given the high SFA intake and the unfavourable cardiovascular statistics in Hungary, the consumption frequency and portion size control of these products are advised. Key messages Monitoring the changes of food composition is important in order to evaluate the effect of the regulation. Manufacturers should be encouraged to reduce the SFA content to a technologically feasible level.

Download Full-text

Renin–angiotensin system blocker use and the risk of acute kidney injury after colorectal cancer surgery: a population-based cohort study

BMJ Open ◽

10.1136/bmjopen-2019-032964 ◽

2019 ◽

Vol 9 (11) ◽

pp. e032964

Author(s):

Charlotte Slagelse ◽

H Gammelager ◽

Lene Hjerrild Iversen ◽

Kathleen D Liu ◽

Henrik T Toft Sørensen ◽

...

Keyword(s):

Colorectal Cancer ◽

Acute Kidney Injury ◽

Cohort Study ◽

Angiotensin Receptor Blockers ◽

Kidney Injury ◽

Population Based ◽

Adjusted Risk ◽

Increased Risk ◽

The Impact ◽

Postoperative Aki

ObjectivesIt is unknown whether preoperative use of ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARBs) affects the risk of acute kidney injury (AKI) after colorectal cancer (CRC) surgery. We assessed the impact of preoperative ACE-I/ARB use on risk of AKI after CRC surgery.DesignObservational cohort study. Patients were divided into three exposure groups—current, former and non-users—through reimbursed prescriptions within 365 days before the surgery. AKI within 7 days after surgery was defined according to the current Kidney Disease Improving Global Outcome consensus criteria.SettingPopulation-based Danish medical databases.ParticipantsA total of 9932 patients undergoing incident CRC surgery during 2005–2014 in northern Denmark were included through the Danish Colorectal Cancer Group Database.Outcome measureWe computed cumulative incidence proportions (risk) of AKI with 95% CIs for current, former and non-users of ACE-I/ARB, including death as a competing risk. We compared current and former users with non-users by computing adjusted risk ratios (aRRs) using log-binomial regression adjusted for demographics, comorbidities and CRC-related characteristics. We stratified the analyses of ACE-I/ARB users to address any difference in impact within relevant subgroups.ResultsTwenty-one per cent were ACE-I/ARB current users, 6.4% former users and 72.3% non-users. The 7-day postoperative AKI risk for current, former and non-users was 26.4% (95% CI 24.6% to 28.3%), 25.2% (21.9% to 28.6%) and 17.8% (17.0% to 18.7%), respectively. The aRRs of AKI were 1.20 (1.09 to 1.32) and 1.16 (1.01 to 1.34) for current and former users, compared with non-users. The relative risk of AKI in current compared with non-users was consistent in all subgroups, except for higher aRR in patients with a history of hypertension.ConclusionsBeing a current or former user of ACE-I/ARBs is associated with an increased risk of postoperative AKI compared with non-users. Although it may not be a drug effect, users of ACE-I/ARBs should be considered a risk group for postoperative AKI.

Download Full-text

Cancer Risk in Children and Young Adults (Offspring) Born after Medically Assisted Reproduction: A Systematic Review and Meta-Analysis

J ◽

10.3390/j2040028 ◽

2019 ◽

Vol 2 (4) ◽

pp. 430-448

Author(s):

Manuela Chiavarini ◽

Andrea Ostorero ◽

Giulia Naldini ◽

Roberto Fabiani

Keyword(s):

Cancer Risk ◽

Health Outcomes ◽

Childhood Cancer ◽

Assisted Reproduction ◽

Meta Analysis ◽

Cancer Data ◽

Medically Assisted Reproduction ◽

Increased Risk ◽

Risk Of Cancer ◽

The Impact

Many studies have investigated the relationship between medically assisted reproduction (MAR) and health outcomes, particularly cancer, in the offspring. This meta-analysis investigated the association between MAR and childhood cancer. Data sources were PubMed, Scopus, and Web of Science up until June 2018. From the selected studies, we extracted the cancer risk estimates of the exposure of interest (MAR, assisted reproductive technology—ART, and in fitro fertilization—IVF). We conducted the meta-analysis using a random effects model. The outcomes of interest were childhood cancers, classified according to the international classification of childhood cancer (ICCC-3). In our meta-analysis (18 cohort and 15 case-control studies) the overall cancer risk was significantly increased in children conceived by MAR, ART, or IVF. MAR and ART significantly increased the risk for hematological tumors, hepatic tumors, and sarcomas (odds ratio (OR) 1.54; 95% CI 1.18–2.02 and OR 1.92; 95% CI 1.34–2.74, respectively). MAR increased acute myeloid leukemia risk (OR 1.41; 95% CI 1.02–1.95) and ART increased neural cancer risk (OR 1.21; 95% CI 1.01–1.46). Our results suggest an increased risk of cancer in children conceived by MAR. Further studies are needed to investigate the impact of fertility treatments, parental subfertility status, and their association on health outcomes in the offspring.

Download Full-text

Mortality and Risk of Cancer After Prophylactic Bilateral Oophorectomy in Women With a Family History of Cancer

JNCI Cancer Spectrum ◽

10.1093/jncics/pky034 ◽

2018 ◽

Vol 2 (3) ◽

Cited By ~ 1

Author(s):

Julie Abildgaard ◽

Magnus Glindvad Ahlström ◽

Gedske Daugaard ◽

Dorte Lisbet Nielsen ◽

Anette Tønnes Pedersen ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Rate Ratio ◽

Bilateral Oophorectomy ◽

Family History Of Cancer ◽

Increased Risk ◽

History Of ◽

Risk Of Cancer ◽

The Impact ◽

History Of Cancer

Abstract Background Current international guidelines recommend systemic hormone therapy (HT) to oophorectomized women until the age of natural menopause. Despite an inherited predisposition to estrogen-dependent malignancies, the guidelines also apply to women oophorectomized because of a family history of cancer. The objective of this study was to investigate the impact of HT on mortality and risk of cancer in women oophorectomized because of a family history of cancer. Methods A nationwide, population-based cohort was used to study women oophorectomized because of a family history of cancer (n = 2002). Comparison cohorts included women from the background population individually matched on age (n = 18 018). Oophorectomized women were subdivided into three groups: oophorectomized at 1) age 45 years or younger not using HT, 2) age 45 years or younger using HT, 3) older than age 45 years, and their respective population comparison cohorts. Results Women oophorectomized at age 45 years or younger using HT had increased overall mortality (mortality rate ratio [MRR] = 3.45, 95% confidence interval [CI] = 1.53 to 7.79), mortality because of cancer (MRR = 5.67, 95% CI = 1.86 to 17.34), and risk of overall cancer (incidence rate ratio [IRR] = 3.68, 95% CI = 1.93 − 6.98), primarily reflected in an increased risk of breast cancer (IRR = 4.88, 95% CI = 2.19 − 10.68). Women oophorectomized at age 45 years or younger not using HT and women oophorectomized at older than age 45 years did not have increased mortality, mortality because of cancer, or risk of overall cancer, but they had increased risk of breast cancer (IRR = 2.64, 95% CI = 1.14 to 6.13, and IRR = 1.72, 95% CI = 1.14 to 2.59, respectively). Conclusions Use of HT in women oophorectomized at age 45 years or younger with a family history of cancer is associated with increased mortality and risk of overall cancer and breast cancer. Our study warrants further investigation to establish the impact of HT on mortality and cancer risk in oophorectomized women with a family history of cancer.

Download Full-text

Communicating Risk Regarding Food Consumption: The Case of Processed Meat

Nutrients ◽

10.3390/nu11020400 ◽

2019 ◽

Vol 11 (2) ◽

pp. 400 ◽

Cited By ~ 2

Author(s):

Slavica Zec ◽

Clara Minto ◽

Carlo Agostoni ◽

Carolina Fano ◽

Honoria Ocagli ◽

...

Keyword(s):

Risk Communication ◽

Public Awareness ◽

Real Data ◽

World Health ◽

International Agency ◽

Processed Meat ◽

Awareness Campaigns ◽

Increased Risk ◽

Health Organization ◽

The Impact

The present research combines real data and parameters found in recent literature that were used to design realistic scenarios demonstrating the potential effects (benefits and costs) of the World Health Organization (WHO)’s risk communication regarding the consumption of processed meat, which was proven to be associated with an increased risk of colorectal cancer (CRC) in an International Agency for Research on Cancer (IARC)/WHO report. The impact of the risk communication of processed meat consumption was simulated using Monte Carlo microsimulation models. The results showed that a 1% reduction in the number of high-level processed meat consumers may lead to a yearly decrease in CRC cases of 406.43 (IC 95%: −243.94, 1056.81), while the more extreme scenario of a 15% reduction may lead to 2086.62 fewer cases (IC 95%: 1426.66, 2746.57). On the other hand, if demand contraction in the processed meat sector resulted in a 0.1% loss in employment, one could expect 27.23 all-cause mortalities attributable to job loss (IC 95%: 16.55, 37.80). This simulation study demonstrates that caution should be taken when implementing public awareness campaigns, particularly when the prevention message is not straightforward.

Download Full-text