The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21448

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes.

Switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complexes are critical regulators of chromatin dynamics during transcription, DNA replication, and DNA repair. A recently identified SWI/SNF subcomplex termed GLTSCR1/1L-BAF (GBAF; or "noncanonical BAF", ncBAF) uniquely contains bromodomain-containing protein BRD9 and glioma tumor suppressor candidate region 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L). Recent studies have identified a unique dependency on GBAF (ncBAF) complexes in synovial sarcoma and malignant rhabdoid tumors, both of which possess aberrations in canonical BAF (cBAF) and Polybromo-BAF (PBAF) complexes. Dependencies on GBAF in malignancies without SWI/SNF aberrations, however, are less defined. Here, we show that GBAF, particularly its BRD9 subunit, is required for the viability of prostate cancer cell lines in vitro and for optimal xenograft tumor growth in vivo. BRD9 interacts with androgen receptor (AR) and CCCTC-binding factor (CTCF), and modulates AR-dependent gene expression. The GBAF complex exhibits overlapping genome localization and transcriptional targets as bromodomain and extraterminal domain-containing (BET) proteins, which are established AR coregulators. Our results demonstrate that GBAF is critical for coordinating SWI/SNF-BET cooperation and uncover a new druggable target for AR-positive prostate cancers, including those resistant to androgen deprivation or antiandrogen therapies. SIGNIFICANCE: Advanced prostate cancers resistant to androgen receptor antagonists are still susceptible to nontoxic BRD9 inhibitors, making them a promising alternative for halting AR signaling in progressed disease.

BRD9 is a critical regulator of androgen receptor signaling and prostate cancer progression

The cellular microenvironment composition and changes therein play an extremely important role in cancer development. Changes in the extracellular matrix (ECM), which constitutes a majority of the tumor stroma, significantly contribute to the development of the tumor microenvironment. These alterations within the ECM and formation of the tumor microenvironment ultimately lead to tumor development, invasion, and metastasis. The ECM is composed of various molecules such as collagen, elastin, laminin, fibronectin, and the MMPs that cleave these protein fibers and play a central role in tissue remodeling. When healthy cells undergo an insult like DNA damage and become cancerous, if the ECM does not support these neoplastic cells, further development, invasion, and metastasis fail to occur. Therefore, ECM-related cancer research is indispensable, and ECM components can be useful biomarkers as well as therapeutic targets. Colorectal cancer specifically, is also affected by the ECM and many studies have been conducted to unravel the complex association between the two. Here we summarize the importance of several ECM components in colorectal cancer as well as their potential roles as biomarkers.

Extracellular Matrix Biomarkers in Colorectal Cancer.

The glycolytic enzyme enolase 2 (ENO2) is dysregulated in many types of cancer. However, the roles and detailed molecular mechanism of ENO2 in colorectal cancer (CRC) metastasis remain unclear. Here, we performed a comprehensive analysis of ENO2 expression in 184 local CRC samples and samples from the TCGA and GEO databases and found that ENO2 upregulation in CRC samples was negatively associated with prognosis. By knocking down and overexpressing ENO2, we found that ENO2 promoted CRC cell migration and invasion, which is dependent on its interaction with the long noncoding RNA (lncRNA) CYTOR, but did not depend on glycolysis regulation. Furthermore, CYTOR mediated ENO2 binding to large tumor suppressor 1 (LATS1) and competitively inhibited the phosphorylation of Yes-associated protein 1 (YAP1), which ultimately triggered epithelial–mesenchymal transition (EMT). Collectively, these findings highlight the molecular mechanism of the ENO2–CYTOR interaction, and ENO2 could be considered a potential therapeutic target for CRC.

/pdf/eno2-promotes-colorectal-cancer-metastasis-by-interacting-pzqesz5t.pdf

ENO2 Promotes Colorectal Cancer Metastasis by Interacting with the LncRNA CYTOR and Activating YAP1-Induced EMT

Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy.

Genetic polymorphisms of 19 autosomal STR loci in 3510 individuals from Han population of Zhejiang province, Southeast China.

Background Colorectal cancer (CRC) is a kind of malignant tumor of digestive system severely affecting human health. The occurrence of CRC is a polygenic and multi-step complex process involving genetic and epigenetic alterations. ADAM12 (a disintegrin and metalloproteases 12), is a gene that was commonly hypermethylated in esophageal cancer using whole-genome methylation microarray in our previous study. Methods We detected the methylation frequencies of the CpG island in ADAM12 promoter using bisulfite-pyrosequencing in CRC cell lines and tissue samples. The expression of ADAM12 was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). A systematic and comprehensive analysis of relationship of DNA hypermethylation and ADAM12 expression in CRC was performed in our samples and TCGA database. Results The expression of ADAM12 in hypermethylated cell lines was significantly lower than that in hypomethylated cell lines, and demethylation agent 5-Aza-dC could demethylate ADAM12 promoter region and reactivate ADAM12 expression effectively. In 74 pairs of colorectal cancer and normal tissues, bisulfite-pyrosequencing results showed significantly hypermethylation of ADAM12 in CRC compared with adjacent normal mucosa, accompanied with lower expression of ADAM12 in CRC tissues compared to that of the normal tissues. In addition, there was a statistically significant negative correlation between ADAM12 protein expression and methylation levels (rho =-0.28, p = 0.015). Conclusion Promoter hypermethylation was probably a mechanism of ADAM12 epigenetic silencing in CRC.

Methylation status of ADAM12 promoter are associated with its expression levels in colorectal cancer.

The expression of ADAMTS14 is regulated by promoter DNA methylation and is associated with poor prognosis in colorectal cancer.

Frameshift mutations frequently occur in colorectal cancer (CRC) with microsatellite instability (MSI), but the nature and biological function of many MSI-associated mutations remain elusive. Here, an MSI frameshift mutation is identified in glioma tumor suppressor candidate region gene 1 (GLTSCR1) that produces two C-terminal-truncated proteins. Additionally, GLTSCR1 is verified as a tumor suppressor that inhibits CRC metastasis. Through binding to bromodomains and the phosphorylation-dependent interaction domain of bromodomain protein 4 (BRD4) via the C-terminus, GLTSCR1 blocks oncogenic transcriptional elongation. However, truncated GLTSCR1 translocates into the cytoplasm and loses BRD4 binding domain, which induces the phosphorylation of RNA Pol II at Ser2 and dephosphorylation at Ser5, then increases oncogenic transcriptional elongation. Importantly, GLTSCR1 deficiency decreases sensitivity to bromodomain and extra terminal domain inhibitors. This study highlights the molecular mechanism of the GLTSCR1-BRD4 interaction, which is a potential therapeutic target for CRC.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/advs.201901114

GLTSCR1 Negatively Regulates BRD4‐Dependent Transcription Elongation and Inhibits CRC Metastasis

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Genetic polymorphisms of 19 autosomal STR loci in 3510 individuals from Han population of Zhejiang province, Southeast China.

Methylation status of ADAM12 promoter are associated with its expression levels in colorectal cancer.

The expression of ADAMTS14 is regulated by promoter DNA methylation and is associated with poor prognosis in colorectal cancer.

GLTSCR1 Negatively Regulates BRD4‐Dependent Transcription Elongation and Inhibits CRC Metastasis