The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field.

Synthetic lethal therapies for cancer: what's next after PARP inhibitors?

Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra-patient heterogeneity. Subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ITH). Since Nowell proposed the clonal evolution of tumor cell populations in 1976, tumor heterogeneity, especially ITH, was actively studied. Research has focused on the genetic basis of cancer, particularly mutational activation of oncogenes or inactivation of tumor-suppressor genes (TSGs). The phenomenon of ITH is commonly explained by Darwinian-like clonal evolution of a single tumor. Despite the monoclonal origin of most cancers, new clones arise during tumor progression due to the continuous acquisition of mutations. It is clear that disruption of the "epigenetic machinery" plays an important role in cancer development. Aberrant epigenetic changes occur more frequently than gene mutations in human cancers. The epigenome is at the intersection of the environment and genome. Epigenetic dysregulation occurs in the earliest stage of cancer. The current trend of epigenetic therapy is to use epigenetic drugs to reverse and/or delay future resistance to cancer therapies. A majority of cancer therapies fail to achieve durable responses, which is often attributed to ITH. Epigenetic therapy may reverse drug resistance in heterogeneous cancer. Complete understanding of genetic and epigenetic heterogeneity may assist in designing combinations of targeted therapies based on molecular information extracted from individual tumors.

/pdf/epigenetic-heterogeneity-in-cancer-4o1txdvf1z.pdf

Epigenetic heterogeneity in cancer

RHO GTPases have been traditionally associated with protumorigenic functions. While this paradigm is still valid in many cases, recent data have unexpectedly revealed that RHO proteins can also play tumor suppressor roles. RHO signaling elements can also promote both pro- and antitumorigenic effects using GTPase-independent mechanisms, thus giving an extra layer of complexity to the role of these proteins in cancer. Consistent with these variegated roles, both gain- and loss-of-function mutations in RHO pathway genes have been found in cancer patients. Collectively, these observations challenge long-held functional archetypes for RHO proteins in both normal and cancer cells. In this review, I will summarize these data and discuss new questions arising from them such as the functional and clinical relevance of the mutations found in patients, the mechanistic orchestration of those antagonistic functions in tumors, and the pros and cons that these results represent for the development of RHO-based anticancer drugs.

RHO GTPases in cancer: known facts, open questions, and therapeutic challenges.

Rationale: Peritoneal metastasis predicts poor prognosis of gastric cancer (GC) patients, and the underlying mechanisms are poorly understood. Methods: The 2-DIGE, MALDI-TOF/TOF MS and single-cell transcriptome were used to detect differentially expressed proteins among normal gastric mucosa, primary GC and peritoneal metastatic tissues. Lentiviruses carrying shRNA and transcription activator-like effector nuclease technology were used to knock down myosin heavy chain 9 (MYH9) expression in GC cell lines. Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, co-immunoprecipitation, and assays for chromatin immunoprecipitation, dual luciferase reporter, agarose-oligonucleotide pull-down, flow cytometry and cell anoikis were performed to uncover nuclear MYH9-induced β-catenin (CTNNB1) transcription in vitro. Nude mice and conditional transgenic mice were used to investigate the findings in vivo. Results: We observed that MYH9 was upregulated in metastatic GC tissues and was associated with a poor prognosis of GC patients. Mechanistically, we confirmed that MYH9 was mainly localized in the GC cell nuclei by four potential nuclear localization signals. Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. Staurosporine reduced nuclear MYH9 S1943 phosphorylation to inhibit CTNNB1 transcription, Wnt/β-catenin signaling activation and GC progression in both orthotropic xenograft GC nude mouse and transgenic GC mouse models. Conclusion: This study identified that nuclear MYH9-induced CTNNB1 expression promotes GC metastasis, which could be inhibited by staurosporine, indicating a novel therapy for GC peritoneal metastasis.

Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis.

Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing (N = 41), RNA sequencing (N = 29), and methylation analysis (N = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes including ATRX, JAK1, NF1, NTRK1, and novel oncogenic BRAF fusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS.

/pdf/integrated-genetic-and-epigenetic-analysis-of-3496t39akf.pdf

Integrated genetic and epigenetic analysis of myxofibrosarcoma

Mucinous gastric carcinoma (MGC) is a unique subtype of gastric cancer with a poor survival outcome. Comprehensive molecular profiles and putative therapeutic targets of MGC remain undetermined. We subjected 16 tumour-normal tissue pairs to whole-exome sequencing (WES) and an expanded set of 52 tumour-normal tissue pairs to subsequent targeted sequencing. The latter focused on 114 genes identified by WES. Twenty-two histologically differentiated MGCs (D-MGCs) and 46 undifferentiated MGCs (U-MGCs) were analysed. Chromatin modifier genes, including ARID1A (21%), MLL2 (19%), MLL3 (15%), and KDM6A (7%), were frequently mutated (47%) in MGC. We also identified mutations in potential therapeutic target genes, including MTOR (9%), BRCA2 (9%), BRCA1 (7%), and ERBB3 (6%). RHOA mutation was detected only in 4% of U-MGCs and in no D-MGCs. MYH9 was recurrently (13%) mutated in MGC, with all these being of the U-MGC subtype (p = 0.023). Three U-MGCs harboured MYH9 nonsense mutations. MYH9 knockdown enhanced cell migration and induced intracytoplasmic mucin and cellular elongation. BCOR mutation was associated with improved survival. In U-MGCs, the MLH1 expression status and combined mutation status (TP53/BCL11B or TP53/MLL2) were prognostic factors. A comparative analysis of driver genes revealed that the mutation profile of D-MGC was similar to that of intestinal-type gastric cancer, whereas U-MGC was a distinct entity, harbouring a different mutational profile to intestinal- and diffuse-type gastric cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.4761

Comprehensive mutation profiling of mucinous gastric carcinoma

Gastric cancer (GC) is one of the most common and life-threatening malignancies. The course of disease and tumor aggressiveness vary among GCs, although how early fate is determined and by what factors remains elusive. To solve this question, we collected 43 gastric intramucosal neoplasias (GINs), comprising dysplasia/intraepithelial neoplasia (D/IEN; a premalignant lesion) and minute GC (miGC; ≤10 mm) of intestinal histotype and performed targeted deep DNA sequencing of 67 GC-related genes derived from large-scale data. Gastric D/IEN was classified into low or high grade (LG-D/IEN or HG-D/IEN). The most frequent mutations in D/IENs included APC (19/25; 76%), ARID2 (6/25; 24%) and MUC6 (5/25; 20%). All LG-D/IENs had APC mutation (12/12) and APC hotspot mutations affecting R1450 and E1554 were noted in both LG-D/IEN and HG-D/IEN. ARID2 mutation always co-occurred with APC mutation, whose tumor variant allele frequency (TVAF) was higher than that of ARID2 in D/IEN. APC and TP53 mutations were mutually exclusive in D/IEN (p = 0.031 [main cohort], p = 0.025 [expanding cohort]) and TP53-mutated D/IEN was exclusively HG-D/IEN (4/4). TP53 mutations were highly recurrent (11/14; 79%) in MLH1-positive miGCs and were detected even in two microscopic lesions measuring 1 and 3 mm, respectively. Furthermore, TVAF analyses suggested that TP53 mutation is the initial event in the TP53-mutated miGCs. In contrast, TP53 mutation was absent (0/4) in MLH1-negative small intramucosal carcinoma (8-24 mm). Advanced GC data suggested that early mutations (APC and TP53) may affect the potential of cancerous progression from D/IEN. This study revealed somatic mutational landscape and initial mutations of GINs, and we report for the first time that TP53 mutations precede other mutations in intestinal-type GC. Our results also indicate that molecular subtyping based on APC/TP53 mutations would be a high-priority approach for determining and predicting the malignant potential of GIN, including D/IEN. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Erika Arakawa

Papers

Integrated genetic and epigenetic analysis of myxofibrosarcoma

Comprehensive mutation profiling of mucinous gastric carcinoma

Initial and crucial genetic events in intestinal-type gastric intramucosal neoplasia.