bims-pimaco 2022-04-17 papers

Cancer Res. 2022 Apr 15. 82(8): 1492-1502

Colorectal Cancer Is Associated with the Presence of Cancer Driver Mutations in Normal Colon.

Julia Matas, Brendan Kohrn, Jeanne Fredrickson, Kelly Carter, Ming Yu, Ting Wang, Xianyong Gui, Thierry Soussi, Victor Moreno, William M Grady, Miguel A Peinado, Rosa Ana Risques.

Although somatic mutations in colorectal cancer are well characterized, little is known about the accumulation of cancer mutations in the normal colon before cancer. Here, we have developed and applied an ultrasensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without colorectal cancer. This testing platform revealed that normal colon from patients with and without colorectal cancer carries mutations in common colorectal cancer genes, but these mutations are more abundant in patients with cancer. Oncogenic KRAS mutations were observed in the normal colon of about one third of patients with colorectal cancer but in none of the patients without colorectal cancer. Patients with colorectal cancer also carried more TP53 mutations than patients without cancer and these mutations were more pathogenic and formed larger clones, especially in patients with early-onset colorectal cancer. Most mutations in the normal colon were different from the driver mutations in tumors, suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals who develop colorectal cancer. These results indicate that somatic evolution contributes to clonal expansions in the normal colon and that this process is enhanced in individuals with cancer, particularly in those with early-onset colorectal cancer.
SIGNIFICANCE: This work suggests prevalent somatic evolution in the normal colon of patients with colorectal cancer, highlighting the potential of using ultrasensitive gene sequencing to predict disease risk.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3607

Nat Commun. 2022 Apr 13. 13(1): 1974

Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer.

Yujun Hao, Baoyu He, Liping Wu, Yamu Li, Chao Wang, Ting Wang, Longci Sun, Yanhua Zhang, Yangyang Zhan, Yiqing Zhao, Sanford Markowitz, Martina Veigl, Ronald A Conlon, Zhenghe Wang.

PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85β disassociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85β recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85β or p85β NLS mutant reduces the growth of tumors harboring a PIK3CA helical domain mutation. Our studies illuminate a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic function. Finally, a combination of Alpelisib, a p110α-specific inhibitor, and an EZH inhibitor, Tazemetostat, induces regression of xenograft tumors harboring a PIK3CA helical domain mutation, but not tumors with either a WT PIK3CA or a PIK3CA kinase domain mutation, suggesting that the drug combination could be an effective therapeutic approach for PIK3CA helical domain mutant tumors.

DOI: https://doi.org/10.1038/s41467-022-29585-x

J Cell Biol. 2022 May 02. pii: e202203136. [Epub ahead of print]221(5):

Establishing spatial control over TORC1 signaling.

Oliver Schmidt, Mariana E G de Araujo.

Target-of-rapamycin complex 1 resides on lysosomes/vacuoles and additionally on signaling endosomes. Gao et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202109084) set out to define the molecular identity of signaling endosomes, along with players required for the formation and maintenance of this endosomal subpopulation.

DOI: https://doi.org/10.1083/jcb.202203136

Int J Mol Sci. 2022 Mar 28. pii: 3706. [Epub ahead of print]23(7):

Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies.

Shaila A Shetu, Debasish Bandyopadhyay.

Mutations of RAS oncogenes are responsible for about 30% of all human cancer types, including pancreatic, lung, and colorectal cancers. While KRAS1 is a pseudogene, mutation of KRAS2 (commonly known as KRAS oncogene) is directly or indirectly associated with human cancers. Among the RAS family, KRAS is the most abundant oncogene related to uncontrolled cellular proliferation to generate solid tumors in many types of cancer such as pancreatic carcinoma (over 80%), colon carcinoma (40-50%), lung carcinoma (30-50%), and other types of cancer. Once described as 'undruggable', RAS proteins have become 'druggable', at least to a certain extent, due to the continuous efforts made during the past four decades. In this account, we discuss the chemistry and biology (wherever available) of the small-molecule inhibitors (synthetic, semi-synthetic, and natural) of KRAS proteins that were published in the past decades. Commercial drugs, as well as investigational molecules from preliminary stages to clinical trials, are categorized and discussed in this study. In summary, this study presents an in-depth discussion of RAS proteins, classifies the RAS superfamily, and describes the molecular mechanism of small-molecule RAS inhibitors.

Keywords: HRAS; KRAS; NRAS; RAS subfamily; cell signaling; colon cancer; heterocycles; lung cancer; mechanism of action; pancreatic cancer; small-molecule inhibitors

DOI: https://doi.org/10.3390/ijms23073706

Mol Med. 2022 Apr 14. 28(1): 42

Roles of ARID1A variations in colorectal cancer: a collaborative review.

Shankun Zhao, Weizhou Wu, Zufu Jiang, Fuqin Tang, Lingzhi Ding, Weifang Xu, Libin Ruan.

Colorectal cancer (CRC), a common malignancy, is one of the leading cause of cancer death in adults. AT-rich interaction domain 1A (ARID1A), a critical portion of the SWItch/sucrose non-fermentation (SWI/SNF) chromatin remodeling complexes, shows one of the most frequent mutant genes across different human cancer types. Deleterious variations of ARID1A has been recognized to be correlated the tumorigenesis and the poor prognosis of CRC. Here, we summarize recent advances in the clinical implications and molecular pathogenesis of ARID1A variations in CRC. According to independent data of 23 included studies, ARID1A is mutated in 3.6-66.7%. Consistently, all of the 23 relevant studies report that ARID1A functions as a specific tumor suppressor in CRC. Clinically, ARID1A variation status serves as a biomarker for survival prognosis and various therapies for CRC. Mechanistically, the pathophysiologic impacts of ARID1A variations on CRC may be associated with the co-occurrence variations of other genes (i.e., TP53, KRAS, APC, FBXW7, and PIK3CA) and the regulation of several signaling pathways being affected (i.e., WNT signaling, Akt signaling, and MEK/ERK pathway), leading to cell cycle arrest, chromatin remodeling, chromosome organization, and DNA hypermethylation of the cancer cells. The present review highlights ARID1A serving as a potent tumor suppressor and an important prognostic factor in CRC. ARID1A variations hint towards a promising tool for diagnostic tumor profiling and individualized therapeutic targets for CRC in the future.

Keywords: ARID1A variations; Biomarker; Colorectal cancer (CRC); Pathogenesis; Prognosis

DOI: https://doi.org/10.1186/s10020-022-00469-6