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
Ykema, B.L.M.; Bisseling, T.M.; Spaander, M.C.W.; Moons, L.M.G.; Biessen-van Beek, D. van der; Saveur, L.; ... ; Leerdam, M.E. van 2021
BackgroundTesticular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors... Show moreBackgroundTesticular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions.MethodsThis prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with >= 3 cycles of cisplatin before age 50. Colonoscopy will be performed >= 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power.DiscussionTC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy.Trial registrationClinical Trials: NCT04180033, November 27, 2019, https://clinicaltrials.gov/ct2/show/NCT04180033. Show less
