Current morphologic features defining advanced adenomas (size >= 10 mm, high-grade dysplasia or >= 25% villous component) cannot optimally distinguish individuals at high risk or low risk of... Show moreCurrent morphologic features defining advanced adenomas (size >= 10 mm, high-grade dysplasia or >= 25% villous component) cannot optimally distinguish individuals at high risk or low risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy-number alterations (CNAs) are associated with adenoma-to-carcinoma progression. We aimed to evaluate whether these molecular features can better predict an individual's risk of me-CRC than the morphologic advanced adenoma features.In this nested case-control study, 529 individuals with a single adenoma at first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy-number profiles were determined, by low-coverage whole-genome sequencing. Prevalence of CNAs in advanced and non-advanced adenomas and its association (OR) with me-CRC was assessed. For the latter, cases (with me-CRC) were matched to controls (without me-CRC) on follow-up, age and sex.CNAs associated with adenoma-to-carcinoma progression were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. me-CRC was statistically significantly associated, also after adjustment for other variables, with age at baseline [OR, 1.14; 95% confidence interval CI), 1.03-1.26; P = 0.012], advanced adenomas (OR, 2.46; 95% CI, 1.50-4.01; P < 0.001) and with the presence of >= 3 DNA copy-number losses (OR, 1.90; 95% CI. 1.02-3.54; P = 0.043).Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger. Show less
Background: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost... Show moreBackground: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups. Methods: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal inamunochemical test (FIT, OC-Sensor, cutoffs: 10/20/47 mu g Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of (sic)20,000 per life-years gained (LYG). Results: Overall, the optimal surveillance strategy was annual FIT (47 mu g) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:(sic)18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 mu g) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER(sic)15,000/ LYG), and when treated with IRT and procarbazine, annual FIT (47 mu g) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:(sic)13,000/LYG). Conclusions: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy. Impact: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors. Show less
Ykema, B.L.M.; Breekveldt, E.C.H.; Carvalho, B.; Wezel, T. van; Meijer, G.A.; Kerst, M.; ... ; Leerdam, M.E. van 2022
Background Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we... Show moreBackground Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR genes. We speculate that this phenomenon could also occur among other cancer survivors. We therefore aim to determine the MMR status and its underlying mechanism in CRC among TCS (TCS-CRC). Methods Thirty TCS-CRC, identified through the Dutch pathology registry, were analysed for MMR proteins by immunohistochemistry. Next-generation sequencing was performed in MMRd CRCs without MLH1 promoter hypermethylation (n = 4). Data were compared with a male cohort with primary CRC (P-CRC, n = 629). Results MMRd was found in 17% of TCS-CRCs vs. 9% in P-CRC (p = 0.13). MMRd was more often caused by somatic double or single hit in MMR genes by mutation or loss of heterozygosity in TCS-CRCs (3/30 (10%) vs. 11/629 (2%) in P-CRCs (p < 0.01)). Conclusions MMRd CRCs with somatic double or single hit are more frequent in this small cohort of TCS compared with P-CRC. Exposure to anticancer treatments appears to be associated with the development of these rare MMRd CRC among cancer survivors. Show less
Martens-De Kemp, S.R.; Komor, M.A.; Hegi, R.; Bolijn, A.S.; Tijssen, M.; Groen, F.L.M. de; ... ; Carvalho, B. 2022
Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-tocarcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was... Show moreGain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-tocarcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma.The miR-17-92 cluster was overexpressed in human colorectal adenoma organoids without 13q gain and downstream effects on mRNA expression were investigated, along with functional consequences in vitro and in vivo.Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, tumor-associated characteristics, such as increased proliferation rate, were not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth.In conclusion, this study showed that miR-17-92 expression contributes to 13q gain-associated adenoma-to-carcinoma progression, however, this is insufficient to cause malignancy. Show less
Background Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia.Aims We evaluated the... Show moreBackground Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia.Aims We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors.Methods In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right-sided, were detected, as published previously. An average-risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy.Results In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size >= 10 mm, whereas (high-grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4-9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient.Conclusions Colorectal neoplasia in HL survivors differ from average-risk controls; classification AN was primarily based on polyp size (>= 10 mm) in HL survivors. Longer follow-up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors. Show less
Hodgkin lymphoma (HL) survivors are at increased risk of developing second primary esophageal squamous cell cancer (ESCC). We aimed to gain insight in the driving events of ESCC in HL survivors ... Show moreHodgkin lymphoma (HL) survivors are at increased risk of developing second primary esophageal squamous cell cancer (ESCC). We aimed to gain insight in the driving events of ESCC in HL survivors (hESCC) by using RNA sequencing and NanoString profiling. Objectives were to investigate differences in RNA signaling between hESCC and sporadic ESCC (sESCC), and to look for early malignant changes in non-neoplastic esophageal tissue of HL survivors (hNN-tissue). We analyzed material of 26 hESCC cases, identified via the Dutch pathology registry (PALGA) and 17 sESCC cases from one academic institute and RNA sequencing data of 44 sESCC cases from TCGA. Gene expression profiles for the NanoString panel PanCancer IO 360 were obtained from 16/26 hESCC and four hNN-tissue, while non-neoplastic squamous tissue of four sporadic cases (sNN-tissue) served as reference profile. Hierarchical clustering, differential expression and pathway analyses were performed. Overall, the molecular profiles of hESCC and sESCC were similar. There was increased immune, HMGB1 and ILK signaling compared to sNN-tissue. The profiles of hNN-tissue were distinct from sNN-tissue, indicating early field effects in the esophagus of HL survivors. The BRCA1 pathway was upregulated in hESCC tissue, compared to hNN tissue. Analysis of expression profiles reveals overlap between hESCC and sESCC, and differences between hESCC and its surrounding hNN-tissue. Further research is required to validate our results and to investigate whether the changes observed in hNN-tissue are already detectable before development of hESCC. In the future, our findings could be used to improve hESCC patient management. Show less
Wanders, L.K.; Cordes, M.; Voorham, Q.; Sie, D.; Vries, S.D. de; d'Haens, G.R.A.M.; ... ; Carvalho, B. 2020
Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer. However, histologically, it is challenging to distinguish between IBD-associated dysplasia from... Show moreInflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer. However, histologically, it is challenging to distinguish between IBD-associated dysplasia from sporadic adenomas. We have molecularly characterized these precursor lesions and show that IBD-associated dysplasia lesions are genomically much more unstable. Show less
Ykema, B.; Rigter, L.; Spaander, M.; Moons, L.; Bisseling, T.; Aleman, B.; ... ; Leerdam, M. van 2020
Background: Hodgkin lymphoma (HL) survivors have an increased colorectal cancer (CRC) risk. Diagnostic accuracy of quantitative fecal immunochemical testing (FIT, OC Sensor) and/or a multi-target... Show moreBackground: Hodgkin lymphoma (HL) survivors have an increased colorectal cancer (CRC) risk. Diagnostic accuracy of quantitative fecal immunochemical testing (FIT, OC Sensor) and/or a multi-target stool DNA test (mt-sDNA, Cologuard®) for advanced neoplasia (AN) was evaluated.Methods: 101 HL survivors underwent a surveillance colonoscopy and were asked to perform two stool tests (FIT and mt-sDNA). Advanced adenoma (AA), advanced serrated lesion (ASL), and AN (AA, ASL, CRC) were evaluated. Sensitivity, specificity, and area under the curve (AUC) for AN were calculated for different FIT cut-offs and mt-sDNA with colonoscopy as reference.Results: FIT and mt-sDNA were analyzed in 73 (72%) and 82 (81%) participants, respectively. AN was detected in 19 (26%) and 22 (27%), respectively. AN sensitivities for FIT cut-off of 10 ug Hb/g feces (FIT10) and mt-sDNA were 37% (95% confidence interval (CI): 16-62) and 68% (95% CI: 45-86), with corresponding specificities of 91% (95% CI: 80-97) and 70% (95% CI: 57-86), respectively. AUC for FIT was 0.68 (95% CI: 0.54-0.82) and for mt-sDNA 0.76 (95% CI: 0.63-0.89).Conclusions: In HL survivors, mt-sDNA showed highest sensitivity but with relatively low specificity for AN. Cost-effectiveness analyses is necessary to determine the optimal surveillance strategy. Show less
Bogie, R.M.M.; Clercq, C.M.C. le; Voorham, Q.J.M.; Cordes, M.; Sie, D.; Rausch, C.; ... ; Sanduleanu, S. 2018
