[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

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Cancer Genome Landscapes

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.

Genetic alterations during colorectal-tumor development.

Mutations in codon 12, 13, or 61 of one of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. Rapid assays for the detection of these point mutations have been developed recently and used to investigate the role mutated ras genes play in the pathogenesis of human tumors. It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly. The highest incidences are found in adenocarcinomas of the pancreas (90%), the colon (50%), and the lung (30%); in thyroid tumors (50%); and in myeloid leukemia (30%). For some tumor types a relationship may exist between the presence of a ras mutation and clinical or histopathological features of the tumor. There is some evidence that environmental agents may be involved in the induction of the mutations.

https://cancerres.aacrjournals.org/content/canres/49/17/4682.full.pdf

ras Oncogenes in Human Cancer: A Review

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

/pdf/the-cancer-genome-atlas-pan-cancer-analysis-project-gw3srsikvs.pdf

The cancer genome atlas pan-cancer analysis project

[Discovery of EML4-ALK, a new gene responsible for lung cancer, and the development of molecular targeted therapy].

Todai OncoPanel (TOP) has been established at The University of Tokyo and consists of DNA (version 3: 464 genes) and RNA panels (version 4: 463 genes). The University of Tokyo Hospital started TOP analysis in February 2017 as a research project approximately in 250 patients. Then, clinical sequencing for advanced solid tumors by TOP panel was performed as Advanced Medical Care Category B in 200 patients toward approval from the Ministry of Health, Labor and Welfare (Patient accrual was completed in December 2019). In this study, we performed TOP analysis in 54 gynecological malignancies and found various types of actionable somatic mutations, gene fusions, germline mutations (in BRCA1, BRCA2, and mismatch repair genes), as well as high tumor mutational burden. We describe the efficacy and the utility of TOP for gynecological malignancies, using our comprehensive analysis of the 54 gynecological malignancy cases. These findings will highlight the usefulness of cancer genomic profiling and shed light on precision medicine in gynecological malignancies.

Cancer Genomic Profiling of Gynecological Malignancies by Todai OncoPanel, a Twin DNA and RNA Panel

e14029 Background: The detection of novel therapeutic targets is increasingly important in oncology. The Todai OncoPanel (TOP) RNA panel is a custom target RNA-seq using the junction capture method to maximize the sensitivity in detecting of known 456 fusion gene transcripts, which is scheduled to be approved for clinical application in Japan in April 2023. Above, TOP RNA panel interrogates aberrantly spliced transcripts and analyzes the expression profiles of 1,390 genes. Malignant brain tumors, including gliomas, require various molecular profiles to be classified based on the latest WHO classification criteria, while their poor prognosis also necessitates new therapeutic targets. In this study, we aimed to classify gliomas and identify the molecular targets by TOP RNA panel. Methods: Among 131 frozen tumor samples of malignant gliomas, 124 samples passed quality control for further validation and were subjected to TOP RNA panel to classify based on the molecular profiles and to identify the molecular targets. Fusion detection and RNA expression analysis were conducted with the original pipeline. Cluster analysis and Gene Set Enrichment Analysis (GSEA) were performed to identify gene sets specific for individual subtypes. Copy numbers of tyrosine kinase genes, MDM2 and CDK4 were evaluated by digital droplet PCR (ddPCR). Results: Among 58 cases of glioblastoma, gene fusions were detected in 11 cases (19.0%) including novel MET fusions, and overexpression of seven tyrosine kinase genes were observed in 21 cases (36.2%). Of the 34 overexpressed genes, gene amplification was observed in 17 genes (50%) by ddPCR. In contrast to IDH-wildtype glioblastoma, IDH-mutant tumors including astrocytomas and oligodendrogliomas hardly harbored fusion genes or gene overexpression. GSEA to compare astrocytomas and oligodendrogliomas identified that the gene sets related to 1p36 and 19q were relatively enriched in astrocytoma, suggesting that regional genomic DNA copy number alterations can be evaluated by gene expression analysis. Conclusions: TOP RNA panel is utilized not only for the detection of molecular targets but also for the molecular classification of glioma, both of which is essential for providing treatments optimized for the individual patients.

Feasibility and utility of the custom RNA-seq for the identification of therapeutic targets and diagnostic biomarkers in glioma.

Genome doubling shapes high-grade transformation and novel EWSR1::LARP4 fusion shows SOX10 immunostaining in hyalinizing clear cell carcinoma of salivary gland.

La presente invention concerne des compositions, des kits, et des procedes pour determiner si des sujets ayant un/des cancer(s) positif(s) pour des mutations de ALK sont susceptibles de repondre au traitement avec un inhibiteur de ALK et/ou si un patient ayant un(de) tel(s) cancer(s) est susceptible d'avoir une evolution de maladie relativement plus lente. Des procedes pour pronostiquer l'evolution d'une maladie chez un sujet ayant un tel cancer sont egalement decrits.

Hiroyuki Mano

Papers

[Discovery of EML4-ALK, a new gene responsible for lung cancer, and the development of molecular targeted therapy].

Cancer Genomic Profiling of Gynecological Malignancies by Todai OncoPanel, a Twin DNA and RNA Panel

Feasibility and utility of the custom RNA-seq for the identification of therapeutic targets and diagnostic biomarkers in glioma.

Genome doubling shapes high-grade transformation and novel EWSR1::LARP4 fusion shows SOX10 immunostaining in hyalinizing clear cell carcinoma of salivary gland.

Identification, évaluation, et thérapie de cancers ayant une résistance innée ou acquise à des inhibiteurs de alk