Mutation heterogeneity between primary gastric cancers and their matched lymph node metastases

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 22; no. 2; pp. 323 - 334
• Main Authors: Lee, Han Hong, Kim, Su Young, Jung, Eun Sun, Yoo, Jinseon, Kim, Tae-Min
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.03.2019; Springer Nature B.V
• Subjects: Abdominal Surgery; Aged; Aged, 80 and over; Cancer Research; Carcinogenesis; Copy number; DNA Mutational Analysis; Female; Gastric cancer; Gastroenterology; Genetic transformation; Genomes; Humans; Invasiveness; Lymph nodes; Lymphatic Metastasis - genetics; Lymphatic Metastasis - pathology; Lymphatic system; Male; Medicine; Medicine & Public Health; Metastases; Metastasis; Microsatellite instability; Middle Aged; Mutation; Oncology; Original Article; p53 Protein; Phenotypes; Phylogeny; Spatial distribution; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Surgical Oncology; Tumors; Lymph node metastasis; Mutations; Gastric cancers; Evolution; Sequencing
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-018-0870-6

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.