Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer

Abstract Background Inflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether IBD susceptibility variants are also associated with skin cancer susceptibility and if such risk is augmented by use of immune-suppressive therapy. Methods The discovery cohort included participants in the UK Biobank. The validation cohort included participants in the Michigan Genomics Initiative. The primary outcome of interest was skin cancer, subgrouped into nonmelanoma skin cancers (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression with matched controls (3 controls:1 case) was performed to identify genomic predictors of skin malignancy in the discovery cohort. Variants with P < .05 were tested for replication in the validation cohort. Validated Single nucleotide polymorphisms were then evaluated for effect modification by immune-suppressive medications. Results The discovery cohort included 10,247 cases of NMSC and 1883 cases of MSC. The validation cohort included 7334 cases of NMSC and 3304 cases of MSC. Twenty-nine variants were associated with risk of NMSC in the discovery cohort, of which 5 replicated in the validation cohort (increased risk, rs7773324-A [DUSP22; IRF4], rs2476601-G [PTPN22], rs1847472-C [BACH2], rs72810983-A [CPEB4]; decreased risk, rs6088765-G [PROCR; MMP24]). Twelve variants were associated with risk of MSC in the discovery cohort, of which 4 were replicated in the validation cohort (increased risk, rs61839660-T [IL2RA]; decreased risk, rs17391694-C [GIPC2; MGC27382], rs6088765-G [PROCR; MMP24], and rs1728785-C [ZFP90]). No effect modification was observed. Conclusions The results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

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Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer

10.1101/2021.03.01.21252521 ◽

2021 ◽

Author(s):

Kelly C. Cushing ◽

Xiaomeng Du ◽

Yanhua Chen ◽

LC Stetson ◽

Annapurna Kuppa ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Skin Cancer ◽

Bowel Disease ◽

Validation Cohort ◽

Disease Risk ◽

Effect Modification ◽

Discovery Cohort ◽

Risk Variants ◽

Increased Risk ◽

Inflammatory Bowel

ABSTRACTBackground and AimsInflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether genomic variants associated with IBD susceptibility are also associated with skin cancer susceptibility and if such risk is augmented by the use of immune-suppressive therapy.MethodsThe discovery cohort included participants in the UK Biobank (n=408,381). The validation cohort included participants in the Michigan Genomics Initiative (n=51,405). The primary outcome of interest was skin cancer, sub-grouped into non-melanoma (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression was performed to identify genomic predictors of skin malignancy. Validated SNPs were evaluated for effect modification by immune-suppressive medication.ResultsThe discovery cohort included 11,079 cases of NMSC and 2,054 cases of MSC. The validation cohort included 7,334 cases of NMSC and 3,304 cases of MSC. Thirty variants were associated with risk of NMSC in the discovery cohort, of which six replicated in the validation cohort [Increased risk: rs7773324-A (DUSP22; IRF4), rs2476601-G (PTPN22), rs1847472-C (BACH2), rs72810983-A (CPEB4); Decreased risk: rs6088765-G (PROCR; MMP24), rs11229555-G (ZFP91-CNTF; GLYAT)]. Twelve variants were associated with risk of MSC in the discovery cohort, of which three replicated in the validation cohort (Increased risk: rs61839660-T (IL2RA); Decreased risk: rs17391694-C (GIPC2; MGC27382), rs6088765-G (PROCR; MMP24)]. No effect modification was observed.ConclusionThe results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

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372 INFLAMMATORY BOWEL DISEASE RISK VARIANTS ARE ASSOCIATED WITH AN INCREASED RISK OF SKIN CANCER

Gastroenterology ◽

10.1016/s0016-5085(21)00919-7 ◽

2021 ◽

Vol 160 (6) ◽

pp. S-72-S-73

Author(s):

Kelly Cushing ◽

Xiaomeng Du ◽

Yanhua Chen ◽

LC Stetson ◽

Annapurna Kuppa ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Skin Cancer ◽

Bowel Disease ◽

Disease Risk ◽

Risk Variants ◽

Increased Risk ◽

Inflammatory Bowel

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Increased Risk for Nonmelanoma Skin Cancers in Patients Who Receive Thiopurines for Inflammatory Bowel Disease

Gastroenterology ◽

10.1053/j.gastro.2011.06.050 ◽

2011 ◽

Vol 141 (5) ◽

pp. 1621-1628.e5 ◽

Cited By ~ 275

Author(s):

Laurent Peyrin–Biroulet ◽

Kiarash Khosrotehrani ◽

Fabrice Carrat ◽

Anne–Marie Bouvier ◽

Jean–Baptiste Chevaux ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Skin Cancers ◽

Increased Risk ◽

Inflammatory Bowel ◽

Nonmelanoma Skin Cancers

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Discovery of a simple two-gene expression biomarker in whole blood predictive of the need for treatment escalation in inflammatory bowel disease

10.1101/2021.07.09.21259804 ◽

2021 ◽

Author(s):

Jan K Nowak ◽

Rahul Kalla ◽

Alex T Adams ◽

Jonas Halfvarson ◽

Jack Satsangi ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Validation Cohort ◽

Inception Cohort ◽

Treatment Intensification ◽

Discovery Cohort ◽

Inflammatory Bowel ◽

Treatment Escalation ◽

Risk Of Treatment

Background and aims: The IBD-Character consortium has recruited large internationally based inception cohorts of treatment-naive inflammatory bowel disease (IBD) patients, providing a unique resource to derive a simple transcriptome signature in the field of prognostication. Methods: The discovery cohort (n=160) was recruited in Norway, Sweden and Spain. The replication inception cohort from the United Kingdom (n=97) was followed-up for a mean (SD) of 350 (228) days. Treatment escalation was formally defined as the need for a biologic agent, ciclosporin and/or surgery, instituted for disease flare after initial remission, or colectomy during the index admission for ulcerative colitis. Whole blood RNA was subject to paired-end sequencing. In the discovery cohort a simple procedure was applied, which exploited differences of transcript ratios. The ten top performing ratios were tested using Cox regression models in the validation cohort. Results: Newly diagnosed IBD patients with high CACNA1E/LRRC42 expression ratio had an increased risk of treatment intensification (validation cohort: HR=19.3, 95%CI 2.6-143.9, p=0.000005; AUC 0.76, 95%CI 0.66-0.86). In 51 patients with CRP < 3.5 mg/L, CACNA1E/LRRC42 still predicted escalation (HR=10.4; 95%CI 1.2-86.5, p=0.007). The second best performing transcript ratio was CACNA1E/CEACAM21 yielding a HR of 10.9 (95%CI 2.5-46.7, p=0.00002) and an AUC of 0.76 (95%CI 0.65-0.86) in the validation cohort. Conclusion: Transcriptomic profiling of an IBD inception cohort identified gene expression ratios CACNA1E/LRRC42 and CACNA1E/CEACAM21 as prognostic biomarkers. These were validated in a replication cohort as strongly associated with short- and long-term risk of treatment intensification and may provide valuable information in clinical decision-making.

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Increased Risk of Nonmelanoma Skin Cancers Among Individuals With Inflammatory Bowel Disease

Gastroenterology ◽

10.1053/j.gastro.2011.07.039 ◽

2011 ◽

Vol 141 (5) ◽

pp. 1612-1620 ◽

Cited By ~ 91

Author(s):

Harminder Singh ◽

Zoann Nugent ◽

Alain A. Demers ◽

Charles N. Bernstein

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Skin Cancers ◽

Increased Risk ◽

Inflammatory Bowel ◽

Nonmelanoma Skin Cancers

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Faculty Opinions recommendation of Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13960983.15418094 ◽

2012 ◽

Author(s):

Severine Vermeire

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Skin Cancers ◽

Increased Risk ◽

Inflammatory Bowel ◽

Nonmelanoma Skin Cancers

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Inflammatory Bowel Disease and Skin Cancer: An Assessment of Patient Risk Factors, Knowledge, and Skin Practices

Journal of Skin Cancer ◽

10.1155/2016/4632037 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Jessica N. Kimmel ◽

Tiffany H. Taft ◽

Laurie Keefer

Keyword(s):

Risk Factors ◽

Inflammatory Bowel Disease ◽

Skin Cancer ◽

Cancer Prevention ◽

Bowel Disease ◽

Skin Cancer Prevention ◽

Indeterminate Colitis ◽

Skin Protection ◽

Increased Risk ◽

Inflammatory Bowel

Objective. Patients with inflammatory bowel disease (IBD) are at increased risk from skin cancer. Aims include assessing IBD patients’ risk factors and knowledge of skin cancer and current skin protection practices to identify gaps in patient education regarding skin cancer prevention in IBD.Methods. IBD patients≥18 years were recruited to complete an online survey.Results. 164 patients (mean age 43.5 years, 63% female) with IBD (67% Crohn’s disease, 31% ulcerative colitis, and 2% indeterminate colitis) were included. 12% (n=19) of patients had a personal history and 34% (n=55) had a family history of skin cancer. Females scored better on skin protection (16.94/32 versus 14.53/32,P≤0.03) and awareness (35.16/40 versus 32.98/40,P≤0.03). Patients over 40 years old scored better on prevention (17.45/28 versus 15.35/28,P=0.03). Patients with skin cancer scored better on prevention (20.56/28 versus 15.75/28,P≤0.001) and skin protection (21.47/32 versus 15.33/32,P≤0.001). 61% of patients recognized the link between skin cancer and IBD.Conclusions. The majority of IBD patients are aware of the link between skin cancer and IBD; however, skin protection practices are suboptimal. This emphasizes the role of healthcare professionals in providing further education for skin cancer prevention in the IBD population.

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