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We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Colorectal Peritoneal metastases (CPM) develop in 15% of colorectal cancers. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS & HIPEC) is the current standard of care in selected patients with limited resectable CPM. Despite selection using known prognostic factors survival is varied and morbidity and mortality are relatively high. There is a need to improve patient selection and a paucity of research concerning the biology of isolated CPM. We aimed to determine the biology associated with transition from primary CRC to CPM and of patients with CPM not responding to treatment with CRS & HIPEC, to identify those suitable for treatment with CRS & HIPEC and to identify targets for existing repurposed or novel treatment strategies. A cohort of patients with CPM treated with CRS & HIPEC was recruited and divided according to prognosis. Molecular profiling of the transcriptome (n = 25), epigenome (n = 24) and genome (n = 21) of CPM and matched primary CRC was performed. CPM were characterised by frequent Wnt/ β catenin negative regulator mutations, TET2 mutations, mismatch repair mutations and high tumour mutational burden. Here we show the molecular features associated with CPM development and associated with not responding to CRS & HIPEC. Potential applications include improving patient selection for treatment with CRS & HIPEC and in future research into novel and personalised treatments targeting the molecular features identified here.

Background More than 70% of patients diagnosed with colorectal cancer with liver metastasis have unresectable disease, so the available treatment is systemic chemotherapy that has limited efficacy and causes harmful side-effects. Thus novel and more effective drugs are needed to improve patients' survival and quality of life. Recent studies have identified several genomic alterations in CRLM that can theoretically be targeted by novel cancer-specific drugs. Among those is the gain-of-function mutations in PIK3CA – the gene encoding the p110a catalytic subunit of PI3K – that are present in 18% of metastatic colorectal tumours. Following the recent FDA-approval of Alpelisib (a PI3Ka-specific inhibitor) HR-positive breast cancer, there is increasing interest to test this drug efficacy to treat CRLM patients with PIK3CA mutations. Although widely used to test cancer cell response, immortalized cell lines fail to represent tumour genomic alterations and heterogeneity. Our goal is to develop patient-derived primary cell models that can be used to reliably test patients' drug response. Methods Fresh colorectal cancer liver metastasis surgical specimens were dissociated and digested into single cells and seeded in matrigel with appropriate culture media. Originated organoid cultures were then submitted to a minimum of 5 passages followed by a freeze-thaw cycle before deemed established culture. To validate organoid tumour origin, we then performed whole-genome sequencing of paired organoid and respective fresh tumour. Results The established patient-derived organoids from colorectal liver metastasis add an overall mutation match of > 80% when compared to with the original tumour. We have found so far two CRLM organoid lines with mutations in the helical domain of PIK3CA (E545A and E542K). Conclusions We have demonstrated patient-derived organoids recapitulate the genome of their tumour of origin. Libraries of these primary cell models should in the near future be used to more accurately determine drug effectiveness prior to clinical trials. Ongoing testing of Alpelisib alone or in combination with other PI3K pathway target genes will determine whether these patients could benefit from these drugs. Legal entity responsible for the study Barros-Silva, J.D. Funding Cancer Research UK. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]