Introduction

Observational studies have indicated that inflammatory bowel disease (IBD) patients have higher incidence of skin carcinoma (SC), including melanoma skin carcinoma (MSC) and nonmelanom skin carcinoma (NMSC) than healthy people. However, whether the correlation is causal remains unclear. The purpose of this study was to evaluate the causality of IBD on SC using the mendelian randomization (MR) analysis.

Aims & Methods

We performed a two-sample MR analysis with public genome-wide association studies (GWAS) data. Eligible instrumental variables (IVs) were selected according to the three assumptions of MR analysis. The inverse-variance weighted (IVW) method was the main method. Complementary methods included the MR-Egger regression, the Weighted Median, the Weighted Mode and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.

Results

Genetically predicted IBD (IVW OR = 1.07, 95% CI: 1.02-1.13, P = 0.011) and ulcerative colitis (UC; IVW OR = 1.09, 95% CI: 1.03-1.16, P = 0.003) was associated with an increased risk of MSC. Results of complementary methods were consistent with those of the IVW method except Weighted mode. In addition, Crohn’s disease (CD; IVW OR = 1.04, 95% CI: 0.99-1.08, P = 0.128) had not a causal effect on MSC. Moreover, IBD (IVW OR = 1.03, 95% CI: 1.00-1.07, P = 0.034) and CD (IVW OR = 1.03, 95% CI: 1.00-1.06, P = 0.045) were associated with a higher risk of NMSC. However, UC (IVW OR = 1.00, 95% CI: 0.97-1.04, P = 0.803) was not associated with NMSC.

Conclusion

Our study revealed genetically predicted associations of IBD on MSC and NMSC in European populations. Additionally, UC increased the risk of MSC, and CD increased the risk of NMSC. But the influence of the use of immunosuppressive agents or biologics cannot be ruled out.

References

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2.Narous M, Nugent Z, Singh H, Bernstein CN. Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis. Inflamm Bowel Dis. 2023 Jul 5;29(7):1047-1056.
3. Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing mendelian randomization investigations. Wellcome Open Res (2019) 4:186.
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5. Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG, Consortium E-I. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol (2015) 30:543–552.
6. Bowden J, Davey SG, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 2016;40(4):304–314.
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Disclosure

There is no conflict of interest.

Introduction

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory bowel disease, whose cause involves the interaction between genetic and environmental factors. At present, the pathogenesis of IBD has not been fully understood. Although there is a recognized link between immune response and IBD, the causal relationship between circulating immune cell counts and IBD remains controversial.

Aims & Methods

This study aimed to elucidate the causal relationship between genetically predicted circulating immune cell counts and IBD. We conducted a bidirectional two-sample Mendelian randomization (MR) study using aggregated statistics from genome-wide association studies. The causal relationship between five circulating leukocytes cells (monocytes, lymphocytes, eosinophils, basophils and neutrophils) counts and IBD, including Ulcerative colitis (UC) and Crohn's disease (CD) was analyzed. Inverse variance weighting (IVW) was used as the primary MR analysis method, and horizontal pleiotropy test and heterogeneity test were used to ensure the stability of the results.

Results

Our findings indicated that monocytes, lymphocytes, eosinophils, and basophils count were not significantly associated with IBD, however, elevated circulating neutrophils count was significantly associated with higher risk of IBD [odds ratio (OR): 1.002; 95% confidence interval (CI): 1.001–1.003; p = 0.009] and UC [OR: 2.465; 95%CI: 1.236–4.916; p = 0.01]. In addition, we also found that IBD [ OR: 12.07; 95% CI: 1.909-76.316; P = 0.008] and UC [OR: 2.465; 95% CI: 1.236 - 4.916; P = 0.01] were significantly associated with higher circulating neutrophils count in reverse MR.

Conclusion

This MR study provides genetic evidence for the causal relationship between the genetically predicted increase in circulating neutrophils count and the risk of IBD (UC and CD). This finding stresses the need for further exploring physiological functions of neutrophils in order to develop effective strategies against IBD.

Disclosure

The authors state that the study was conducted in the absence of any business or financial relationships that could be interpreted as potential conflicts of interest.

Introduction

Chronic inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are associated with an increased risk of various cancers, particularly colorectal cancer, but also other types, such as small intestine, biliary tract, or liver cancers. Additionally, certain extra-digestive cancers may also occur in patients with these conditions. These risks vary depending on the duration and severity of inflammation, as well as other factors such as family history or exposure to certain treatments. This work explores the diversity of cancers associated with IBD, their prevalence, and their clinical characteristics, highlighting the importance of considering these risks in the medical management of patients.

Aims & Methods

This is a retrospective and descriptive single-center study conducted within a hepatogastroenterology department, focusing on patients followed for inflammatory bowel diseases (IBD) who developed cancer. The study covers the period from 1990 to 2025.

Results

Out of a total of 1,795 patients followed for IBD (1,200 for Crohn's disease and 595 for ulcerative colitis), 2% (36 patients) developed cancer. The male-to-female sex ratio was 0.38, with a clear female predominance. Among the patients, 69.4% (25) had Crohn's disease, and 30.55% (11) had ulcerative colitis.
The most common location of Crohn's disease was colonic involvement (44%, 11 cases),the predominant phenotype was inflammatory (52%, 13 cases) ,for ulcerative colitis the most frequent location was left-sided colitis (54%, 6 cases) ,the median disease duration before the onset of cancer was 60 months.
Digestive cancers were the most commonly associated with IBD (38.8%, 14 cases), followed by breast cancer in women (30.5%, 11 cases), gynecological cancers (11.1%, 4 cases), prostate adenocarcinoma (5%, 2 cases), skin cancers (5%, 2 cases), and other cancers (5%, 2 cases).
Only 30.5% (11 patients) had risk factors (chronic smoking, family history of cancer, etc.).
Regarding treatment, 33% (12 patients) were on biologic therapy , 30.5% (11) were on azathioprin , 16.6% (6) were on therapeutic abstention , 8.3% (3) were on aminosalicylates, and 5.5% (2) were on corticosteroids.
Treatment was discontinued in 63.8% (23) of patients after the discovery of cancer, and 22% (8) experienced a flare-up which was successfully managed with corticosteroid therapy.
Eighty-three point three percent (83.3%, 30 patients) underwent surgical treatment alone or in combination with radiochemotherapy. Sixteen point six percent (16.6%, 6 patients) were at an advanced stage and had metastases, so they received palliative treatment.
Thirty-six percent (36%, 13 patients) had a good outcome, 30.5% (11) were lost to follow-up, and 2.7% (1) died.

Conclusion

The study shows a 2% cancer incidence in IBD patients, slightly higher than the general population's risk (0.3–0.5% annually), likely due to prolonged inflammation and disease duration. These findings highlight the need for enhanced cancer surveillance and preventive strategies, especially for patients with colonic involvement.

Introduction

Patients with inflammatory bowel disease (IBD) have an increased risk of developing intestinal and extra-intestinal cancers. Specific therapies used to control inflammation in IBD may have a different impact on cancer risk. However, there are no long-term studies investigating cancer risk in patients with IBD.

Aims & Methods

In the present study we aimed to quantify the overall risk for of developing cancer and to identify specific risk factors for the occurrence of intestinal and extra-intestinal cancers in 560 consecutive patients with Crohn's disease (CD, N=310) or ulcerative colitis (UC, N=250) referred to our outpatient department between January 2021 and February 2022. Demographic data, smoking status, alcohol consumption, age at IBD diagnosis, disease location and course, therapies, and cancer development after IBD diagnosis were recorded. Odds ratios (OR) were estimated by logistic regression analysis. Standardized Incidence Ratios (SIRs) were estimated compared with the general population.

Results

During a median follow-up interval or time of 10 years (range 1-26 years), 6.6% of patients (37/550, female 65 %, mean age 51 years) developed cancer (SIR 1.94, 95%CI 1.4-2.6). The most common cancers were colorectal (12.3%), skin (8.2%), and breast cancer (7.2%). Female patients had an increased risk for all cancers (SIR 3.11, 95%CI 2.06-4.3), melanoma (SIR 5.6, 95%CI 1.14-16.2) and colorectal cancer (SIR 7.59, 95%CI 3-15.4). Male patients had an increased risk of lymphoma (SIR 26.15, 95%CI 3.2-95.7). Younger age at diagnosis of CD (A1 Montreal classification, OR 37.9, 95%CI 10-14), immunosuppressive monotherapy (OR 5.5, 95%CI 2.65- 11) or in combination with anti-TNFα (OR 9.9, 95%CI 3.3-29.09) were associated with an increased risk of cancer in the study population.

Conclusion

We have identified subgroups of IBD patients who would particularly benefit from screening programs. Our findings need to be validated in independent cohorts.

Introduction

Colorectal cancer (CRC) risk is increased in patients with long-standing colitis related to Inflammatory Bowel Disease (IBD). A higher frequency of mucinous and signet-ring colonic adenocarcinoma has been suggested in IBD, but risk factors for these histotypes of CRC are undefined.

Aims & Methods

Primary aim was to compare the frequency of mucinous and signet-ring adenocarcinoma in patients with vs without IBD. Secondary aims were to search for IBD-related risk factors for signet ring and mucinous adenocarcinoma and to compare the localization of these histotypes of CRC in patients with vs without IBD. From January 2002 to January 2023, all IBD patients with concomitant colorectal adenocarcinoma (Cases) were retrospectively enrolled. Each Case was matched with 2 patients with CRC and no IBD (Controls) for age at CRC diagnosis (±5 years). Inclusion criteria for Cases and Controls: 1) age ≥18; 2) well-defined diagnosis of CRC. Additional inclusion criteria for Cases: well-defined diagnosis of IBD, classified according to standard criteria. Exclusion criteria: Missing histological and surgical report. Data were expressed as median [range]. Student-t Test and χ2 test were used for comparisons. Univariate logistic regression model was applied for assessing risk factors for mucinous and signet-ring CRC (OR [95%CI]).

Results

The study population included 120 patients with colorectal adenocarcinoma: 40 IBD patients and 80 non-IBD Controls. CRC in the 40 IBD patients occurred in 24 (60%) patients with Ulcerative Colitis (UC) and in 16 (40%) with Crohn’s Disease (CD). In patients with CRC, no differences were observed between IBD and non-IBD Controls in terms of gender (F) (13 [32.5%] vs 35 [43.7%]; p=0.32) and median age at diagnosis of CRC (54 [29-80] vs 58 [31-83] years; p=0.19). CRC in IBD was histologically defined as mucinous/ signet-ring in 17 (42.5%) and standard adenocarcinoma in 23 (57.5%) patients. Mucinous/signet ring CRC more frequently occurred in patients with IBD vs non-IBD Controls (17 [42.5%] vs 18 [22.5%], p=0.03). In IBD patients, rectal localization of CRC was significantly more frequent in mucinous/signet-ring vs standard CRC (4 [17.4%] vs 8 [47.1%]; p=0.04). In stricturing CD, there was a significantly higher frequency of standard vs mucinous/signet-ring CRC (7 [77.8%] vs 1 [14.4%]; p=0.04). Other IBD characteristics did not differ in relation to the 2 CRC histotypes, including gender (F): 8 [34.8%] vs 5 [29.4%]; p=0.98 and IBD duration at CRC diagnosis (14 [1-45] vs 17 [1-36]; p=0.74). In IBD, CRC stage at diagnosis was comparable between patients with standard vs mucinous/signet-ring CRC (stage I: 6 [26.1%] vs 1 [5.9%]; p=0.21; II: 9 [39.1%] vs 4 [23.5%]; p=0.48; III: 5 [21.7%] vs 7 [41.2%]; p=0.71; IV: 3 [13.1%] vs 5 [29.4%]; p=0.37)). At univariate analysis, no IBD-related risk factors for mucinous/signet-ring CRC were detected.

Conclusion

In the tested cohort, mucinous and signet-ring adenocarcinoma was more frequently observed in IBD than in non-IBD controls, although no IBD-related risk factors were identified. A higher frequency of rectal involvement is suggested for mucinous/signet-ring vs standard adenocarcinoma in IBD.

Introduction

Inflammatory Bowel Diseases (IBD) patients are associated to a higher risk of developing colonic dysplasia and colorectal cancer due to long-standing colonic inflammation and immunosuppressant therapies. They seem to have also a higher risk of developing extra-intestinal malignancies, such as cholangiocarcinoma, skin cancer, and others. Different studies have been conducted to assess whether a correlation exists between IBD, medical treatments and cancers, but the results are controversial.

Aims & Methods

Our study aimed to evaluate the risk factors of malignancies in our IBD patients, particularly considering the medication history.
In this single-center retrospective study, IBD patients with a history of at least one malignancy post-IBD diagnosis followed at the Gastroenterology Unit of Azienda Ospedale Università Padova were enrolled (cases). Demographics and clinical data, including medication information, were collected before and at the time of malignancy diagnosis. A group of IBD patients, matched by sex and age, without a malignancy history were also included (controls), considering the medications taken before and at the time of the last visit for comparison.

Results

Among 2213 IBD patients followed at our center (1212 males, 1040 CD, and 1173 UC), 153 cases (80 UC and 73 CD, 46.4% males, mean age at diagnosis: 38.4±14.7) and 50 sex and matched controls were included (30 UC and 20 CD, 52% males, mean age at diagnosis: 38.9±0.8). Twelve patients had two malignancies, and 2 had three. For the scope of our study, we considered only the first tumor. Results are shown in the Table 1. The mean time from IBD diagnosis to the first tumor was 15 years (SD 10.5). Considering malignancies, the most frequent in our population were breast cancer (27/1001 females, 2.7%), colorectal cancer (23/2213, 1%), melanoma (24/2213, 1.1%), and non-melanoma skin cancer (15/2213, 0.7%). Patients with colon cancer were younger at the time of IBD diagnosis (31.0±15.8 vs. 38.9±0.8), while patients with prostate and urinary cancer (11/2213, 0.5%) were older compared to controls (49.6±13.7 vs. 38.9±0.8). A lower percentage of patients with colon (13%), breast (4%), and prostate cancers (9.1%) had taken biological therapy before cancer occurrence, as compared to controls (44%, p<0.01). Finally, we observed a significantly higher number of melanoma and breast cancer patients taking azathioprine (AZA) at the time of cancer diagnosis for more than 4 years. No difference in terms of duration of AZA and biological therapies before cancer diagnosis was observed.

Table 1: Type and frequency of Malignancies and characteristics of the patients

Conclusion

Our study found that biological therapy was not associated to malignancies, while azathioprine use was associated with breast and melanoma cancers. A younger age at diagnosis was associated with colon cancer, while an older age with prostate and urinary cancers.

Introduction

While genetic susceptibility and environmental exposures are known contributors to the pathophysiology of Inflammatory Bowel Disease (IBD), their complex gene-environment interactions (GXE) remain elusive. This systematic review aims to summarize the current evidence of GXE in IBD.

Aims & Methods

PubMed, EMBASE, Web of Science and Scopus were systematically searched from inception through July 20, 2022 to identify publications examining the interaction effect of genetic variants and environmental factors in IBD. All eligible studies were graded using the STREGA guideline.

Results

4,305 publications were identified and screened, resulting in 36 eligible studies. 17 studies reported statistically significant interactions.
NOD2-smoking interaction was most frequently investigated and showed variant-specific effects at rs2066847 regarding the risk of Crohn’s disease. Gene-smoking interactions were further identified in other IBD risk genes (ATG16L1, IL23R, and CALM3), detoxification genes (GSTP1 and ΗΜΟΧ1), smoking-associated genes (CHRNA3, CHRNA5, PPP1R3C, and BDNF), and the inflammatory cytokine (IL1B) through a candidate gene approach. Immunochip-wide interaction analyses yielded 64 smoking interacting variants.
Gene-diet interactions were observed across multiple nutritional measures, including fatty acid intake with CYP4F3 and FADS2, serum selenium with SEPHS1 and SEPSECS, potassium intake with IL21, alcohol consumption with IL12B, heme iron intake with FCGR2A and serum vitamin D with VDR.

Conclusion

Although previous studies have provided valuable insights into potential roles of GXE in the etiology of IBD, current evidence is sparse and inconclusive due to limited statistical power and lack of replication. Further studies, including genome wide environment interaction studies (GWEIS) and genotype-based nutrition/lifestyle clinical trials, are needed to unravel the missing heritability influenced by environmental exposures, and to construct personalized recommendations of lifestyle/dietary modification based on an individual genetic background.