Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors

Abstract

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 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.

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum‐based chemotherapy

“…We hypothesize that the development of CRC in TCS may differ from that observed in the general population due to (epi)genetic changes caused by specific anticancer treatments 8 . Increasing evidence suggests that sporadic CRCs result from the stepwise accumulation of multiple somatic mutations, which is also observed in CRCs in TCS 25 . Kuijk et al showed that both capecitabine–oxaliplatin chemotherapy and radiotherapy are mutagenic in colorectal stem cells and that the mutational burden was significantly increased in normal noncancerous cells, in addition to the typical accumulation of mutations associated with aging, applying whole genome sequencing 26 .…”

“…8 Increasing evidence suggests that sporadic CRCs result from the stepwise accumulation of multiple somatic mutations, which is also observed in CRCs in TCS. 25 Kuijk et al showed that both capecitabine-oxaliplatin chemotherapy and radiotherapy are mutagenic in colorectal stem cells and that the mutational burden was significantly increased in normal noncancerous cells, in addition to the typical accumulation of mutations associated with aging, applying whole genome sequencing. 26 They found the pattern of single base substitutions (SBS) to be consistent with an SBS mutational signature from the Catalogue of Somatic Mutations in Cancer that has been ascribed to prior platinum-based treatment.…”

“…The median time between TC treatment (last cycle of platinum-based treatment) and colonoscopy was 20 years (IQR: [16][17][18][19][20][21][22][23][24][25][26]. Median age at colonoscopy was 50 years (IQR 43-57 years).…”

New insights on testicular cancer prevalence with novel diagnostic biomarkers and therapeutic approaches

“…Stage I nonseminomas had a good prognosis, with 99.1% of disease‐specific 15‐year survivors. It is treatable with active surveillance 129 . Post‐orchiectomy treatment for stage II and III non‐seminomas includes cisplatin‐dependent chemotherapy and RPLND, depending on lymph node linkage and whether tumor biomarkers stay high after orchiectomy.…”

“…It is treatable with active surveillance. 129 Post‐orchiectomy treatment for stage II and III non‐seminomas includes cisplatin‐dependent chemotherapy and RPLND, depending on lymph node linkage and whether tumor biomarkers stay high after orchiectomy. For stage II nonseminoma, chemotherapy with or without RPLND had a 5‐year relapse‐free rate ranging from 96% to 97%.…”