[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.

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The cancer genome atlas pan-cancer analysis project


 Background: DNAs extracted from formalin-fixed and paraffin-embedded (FFPE) tissues are fragmented and contain a significant amount of single-stranded DNA (ssDNA). We found that most of the false-positive mutations in clinical sequencing with FFPE samples are ssDNA-derived artifacts. During the end-repair step of library preparation, chimeric reads are generated by mis-annealing of ssDNA molecules comprising homologous sequences with a mismatched base. The mismatched base is called as a false-positive mutation, and the position of the base is biased towards the effective ends in the individual reads because either side of the chimeric read should be soft-clipped by the mapping pipeline. Based on this theory, we developed a post hoc filter, MicroSEC, to predict such artifacts in FFPE samples.
 Methods: Fifty-three fresh frozen (FF) and 190 FFPE normal breast tissue samples and 23 FF and 33 FFPE breast cancer samples were obtained from 26 patients, and subjected to capture-based panel sequencing (Todai OncoPanel, TOP). We also obtained TOP data from 54 FFPE various tumor samples. MicroSEC was developed to predict artifacts with BAM files based on the positional bias of mutations within each read. The predictions were validated with amplicon-based sequencing of 97 mutations. We also developed a model which predicts artifacts only from the mutated base information without corresponding BAM files, by using 5,034 MicroSEC predictions as the supervised data with the LightGBM technique. A total of 742,030 mutations from the AACR Project GENIE were examined with the model. Results: Among the normal breast tissues, we identified 0.3 and 11.7 somatic mutations per sample in FF and FFPE specimens, and 0 (0%) and 10.1 (86.0%) were filtered out by MicroSEC, respectively. Two unique mutations with variant allele frequency of >50% in FFPE samples were eliminated. From the breast cancer specimens, we identified 4.0 and 10.7 mutations per sample in FF and FFPE, and 0 (0%) and 3.2 (30.2%) were filtered out, respectively. In the clinical sequencing data of 54 FFPE tumor samples, we identified 21.6 mutations per sample and 3.6 (16.6%) including five unique pathogenic mutations were filtered out. The validation study showed that the sensitivity and specificity for artifacts of MicroSEC were 97% (95% confidence interval (CI): 82%-100%) and 96% (95% CI: 88%-99%), respectively. Further, the prediction model reproduced the MicroSEC predictions with an area under the ROC curve of 0.995. The model detected 2,512 mutations (0.34%) as artifacts from Project GENIE data. There was a difference in the artifact detection rate between institutions, and 815 (1.45%) of the 56,100 mutations reported by UCSF were predicted as artifacts.
 Conclusions: MicroSEC removes only FFPE artifacts without eliminating true mutations found in FF samples. Our pipeline will increase the reliability of the clinical sequencing and advance cancer research using FFPE samples.
 Citation Format: Masachika Ikegami, Shinji Kohsaka, Takeshi Hirose, Toshihide Ueno, Satoshi Inoue, Naoki Kanomata, Hideko Yamauchi, Taisuke Mori, Shigeki Sekine, Yoshihiro Inamoto, Yasushi Yatabe, Hiroshi Kobayashi, Sakae Tanaka, Toru Akiyama, Tomotake Okuma, Hiroyuki Mano. MicroSEC: Sequence error filter for formalin-fixed and paraffin-embedded samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2185.

Abstract 2185: MicroSEC: Sequence error filter for formalin-fixed and paraffin-embedded samples

Discovery of the EML4-ALK fusion-type oncogene had triggered extensive search for tyrosine kinase fusions in lung cancer (and other cancer types), resulting in the identification of various ALK-, ROS1-, RET-, FGFR1/2/3- and other kinase gene-fusions. Marked therapeutic efficacy of ALK inhibitors was swiftly confirmed in patients with ALK-rearranged tumours, and some of the compounds are already brought to the clinics. Likewise, specific inhibitors for each fusion kinase are currently under clinical investigation. Lung cancer is thus one of the tumour types that identification of fusion genes has most contributed to improve directly the treatment strategies for.

Chromosomal Translocations in Lung Cancer

NOVEMBER 2022 CANCER DISCOVERY | 2509 Summary: Since June 2019, under the umbrella of the national health insurance system, Japan has started cancer genomic medicine (CGM) with comprehensive genomic profiling (CGP) tests. The Ministry of Health, Labour and Welfare (MHLW) of Japan constructed a network of CGM hospitals (a total of 233 institutes as of July 1, 2022) and established the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter for CGM. Clinical information and genomic data from the CGP tests are securely transferred to C-CAT, which then generates “C-CAT Findings” reports containing information of clinical annotation and matched clinical trials based on the CGP data. As of June 30, 2022, a total of 36,340 datapoints of clinical/genomic information are aggregated in C-CAT, and the number is expected to increase swiftly. The data are now open for sharing with not only the CGM hospitals but also other academic institutions and industries. PERSPECTIVE

The CAncer Genomic Test Standardized Format : A Unified File Format to Summarize Genomic Aberrations

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[108th Scientific Meeting of the Japanese Society of Internal Medicine: panel discussion: 2. Discovery and clinical application of a novel oncogene in lung cancer].

Hiroyuki Mano

Papers

Abstract 2185: MicroSEC: Sequence error filter for formalin-fixed and paraffin-embedded samples

Chromosomal Translocations in Lung Cancer

The CAncer Genomic Test Standardized Format : A Unified File Format to Summarize Genomic Aberrations

[108th Scientific Meeting of the Japanese Society of Internal Medicine: panel discussion: 2. Discovery and clinical application of a novel oncogene in lung cancer].

Cancer Genomic Medicine: Today and the Future