Han Hong Lee1,2, Su Young Kim3, Eun Sun Jung4, Jinseon Yoo2,5, Tae-Min Kim6,7. 1. Division of Gastrointestinal Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 2. Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 3. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 4. Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 5. Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Socho-Gu, Banpo-Ro 222, Seoul, 06591, South Korea. 6. Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea. tmkim@catholic.ac.kr. 7. Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Socho-Gu, Banpo-Ro 222, Seoul, 06591, South Korea. tmkim@catholic.ac.kr.
Abstract
BACKGROUND: The acquisition of an invasive phenotype by a tumor cell is a crucial step of malignant transformation. The underlying genetic mechanisms in gastric cancer (GC) are not well understood. METHODS: We performed whole-exome sequencing of 15 pairs of primary GC and their matched lymph node (LN) metastases (10 primary GCs with single matched LNs and 5 primary GCs with three LNs per case, respectively). Somatic alterations including single nucleotide variations, short insertions/deletions including locus-level microsatellite instability and copy number alterations were identified and compared between the primary and metastatic LN genomes. RESULTS: Mutation abundance was comparable between the primary GC and LN metastases, but the extent of mutation overlap or the mutation heterogeneity between primary and LN genomes varied substantially. Primary- or LN-specific mutations could be distinguished from common mutations in terms of mutation spectra and functional categories, suggesting that the mutation forces are not constant during gastric carcinogenesis. A spatial distribution revealed TP53 mutations as common mutations along with a number of region-specific mutations, such as primary-specific SMARCA4 and LN-specific CTNNB1 mutations. The subclonal architectures of common mutations were largely conserved between primary GC and LN metastatic genomes. The mutation-based phylogenetic analyses further showed that LN metastases may have arisen from homogeneous subclones of primary tumors. CONCLUSIONS: The abundance and spatial distribution of mutations may provide clues on the evolutionary relationship between primary and matched LN genomes. Gene-level analyses further distinguished the early addicted cancer drivers such as TP53 mutations from late acquired region-specific mutations.
BACKGROUND: The acquisition of an invasive phenotype by a tumor cell is a crucial step of malignant transformation. The underlying genetic mechanisms in gastric cancer (GC) are not well understood. METHODS: We performed whole-exome sequencing of 15 pairs of primary GC and their matched lymph node (LN) metastases (10 primary GCs with single matched LNs and 5 primary GCs with three LNs per case, respectively). Somatic alterations including single nucleotide variations, short insertions/deletions including locus-level microsatellite instability and copy number alterations were identified and compared between the primary and metastatic LN genomes. RESULTS: Mutation abundance was comparable between the primary GC and LN metastases, but the extent of mutation overlap or the mutation heterogeneity between primary and LN genomes varied substantially. Primary- or LN-specific mutations could be distinguished from common mutations in terms of mutation spectra and functional categories, suggesting that the mutation forces are not constant during gastric carcinogenesis. A spatial distribution revealed TP53 mutations as common mutations along with a number of region-specific mutations, such as primary-specific SMARCA4 and LN-specific CTNNB1 mutations. The subclonal architectures of common mutations were largely conserved between primary GC and LN metastatic genomes. The mutation-based phylogenetic analyses further showed that LN metastases may have arisen from homogeneous subclones of primary tumors. CONCLUSIONS: The abundance and spatial distribution of mutations may provide clues on the evolutionary relationship between primary and matched LN genomes. Gene-level analyses further distinguished the early addicted cancer drivers such as TP53 mutations from late acquired region-specific mutations.
Authors: Christoph Röcken; Anu Amallraja; Christine Halske; Luka Opasic; Arne Traulsen; Hans-Michael Behrens; Sandra Krüger; Anne Liu; Jochen Haag; Jan-Hendrik Egberts; Philip Rosenstiel; Tobias Meißner Journal: Genome Med Date: 2021-11-08 Impact factor: 11.117
Authors: Raghav Sundar; Drolaiz Hw Liu; Gordon Ga Hutchins; Hayley L Slaney; Arnaldo Ns Silva; Jan Oosting; Jeremy D Hayden; Lindsay C Hewitt; Cedric Cy Ng; Amrita Mangalvedhekar; Sarah B Ng; Iain Bh Tan; Patrick Tan; Heike I Grabsch Journal: Gut Date: 2020-11-23 Impact factor: 23.059