EGAGenomicsDAC DBGhttps://ega-archive.org/dacs/EGAC00001000432EGAEGA DAC EGAC00001000432EGAdacdbg@umcutrecht.nlOvarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.Early-onset colorectal cancers (EOCRCs) may have biological or genomic features distinct from late-onset CRCs (LOCRCs). Previous studies have mostly focused on the germline predisposition conditions of EOCRCs, but we hypothesized that EOCRCs may have distinct somatic aberrations that accelerate cancer development. To identify the somatic aberrations that accelerate cancer development at an early age, we conducted whole exome sequencing for 28 polyposis-unrelated, microsatellite stable (MSS) EOCRCs with no known germline predisposition conditions. Surprisingly, we found two distinct groups in the context of mutational burden: 6 hypermutated cases with 2325 to 10973 mutations and 22 nonhypermutated cases with 47 to 154 mutations. Further analysis revealed that four of the six hypermutated cases had the same POLE P286R mutation. We validated this finding in 83 MSS EOCRCs and 27 MSS LOCRCs, which revealed that 7.2% of EOCRCs (6/83) had the POLE P286R mutation, which was not found in LOCRCs. Clinicopathologically, EOCRCs with POLE mutations occurred far more frequently in the right colon than in the left colon, affecting men more frequently than women. In summary, we have identified a unique subclass of colon cancer characterized by a hypermutation associated with the POLE mutation. The acquisition of the POLE mutation leading to hypermutation can accelerate cancer development. Clinically, this subset with hypermutation may be susceptible to immune checkpoint blockade.Developing strategies to enhance cancer prevention is a paramount goal, particularly given recent concerns about surgical treatment of preinvasive states such as ductal carcinoma in situ. Promoting effective immunosurveillance by leukocytes that scan for nascent neoplastic transformations represents a potential means to achieve this goal. Because most breast cancers arise within the ductal epithelium, enhancing protective immunosurveillance will likely necessitate targeting one or more of the distinctive lymphocyte types found in these sites under normal conditions. Here, we have characterized the intraepithelial lymphocyte compartment of non-cancerous human breast tissue and identified a subset of T lymphocytes that can be pharmacologically targeted to enhance their responses to breast cancer cells. Specifically, Vδ2(+) γδ T cells were consistently present in preparations of mammary ductal epithelial organoids and they proliferated in response to zoledronic acid, an aminobisphosphonate drug. Vδ2(+) T cells from breast ductal organoids produced the antitumor cytokine IFNγ and efficiently killed bisphosphonate-pulsed breast carcinoma cells. These findings demonstrate the potential for exploiting the ability of Vδ2(+) γδ T cells to respond to FDA-approved bisphosphonate drugs as a novel immunotherapeutic approach to inhibit the outgrowth of breast cancers.An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity.Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate.The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy.Zumwalde Nicholas A NA, Haag Jill D JD, Sharma Deepak D, Mirrielees Jennifer A JA, Wilke Lee G LG, Gould Michael N MN, Gumperz Jenny E JEAhn Sung-Min SM, Ansari Adnan Ahmad AA, Kim Jihun J, Kim Deokhoon D, Chun Sung-Min SM, Kim Jiyun J, Kim Tae Won TW, Park Inja I, Yu Chang-Sik CS, Jang Se Jin SJKopper Oded O, de Witte Chris J CJ, Lõhmussaar Kadi K, Valle-Inclan Jose Espejo JE, Hami Nizar N, Kester Lennart L, Balgobind Anjali Vanita AV, Korving Jeroen J, Proost Natalie N, Begthel Harry H, van Wijk Lise M LM, Revilla Sonia Aristín SA, Theeuwsen Rebecca R, van de Ven Marieke M, van Roosmalen Markus J MJ, Ponsioen Bas B, Ho Victor W H VWH, Neel Benjamin G BG, Bosse Tjalling T, Gaarenstroom Katja N KN, Vrieling Harry H, Vreeswijk Maaike P G MPG, van Diest Paul J PJ, Witteveen Petronella O PO, Jonges Trudy T, Bos Johannes L JL, van Oudenaarden Alexander A, Zweemer Ronald P RP, Snippert Hugo J G HJG, Kloosterman Wigard P WP, Clevers Hans HfalseDivision of Biomedical Genetics UMC UtrechtData Access Committee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