Comprehensive genomic characterization of sporadic synchronous colorectal cancer: Implications for treatment optimization and clinical outcome

Abstract

Sporadic synchronous colorectal cancer (SCRC) refers to multiple primary CRC tumors detected simultaneously in an individual without predisposing hereditary conditions, which accounts for the majority of multiple CRCs while lacking a profound understanding of the genomic landscape and evolutionary dynamics to optimize its treatment. In this study, 103 primary tumor samples from 51 patients with SCRC undergo whole-exome sequencing. The germline and somatic mutations and evolutionary and clinical features are comprehensively investigated. Somatic genetic events are largely inconsistent between paired tumors. Compared with solitary CRC, SCRCs have higher prevalence of tumor mutation burden high (TMB-H; 33.3%) and microsatellite-instability high (MSI-H; 29.4%) and different mutation frequencies in oncogenic signaling pathways. Moreover, neutrally evolving SCRC tumors are associated with higher intratumoral heterogeneity and better prognosis. These findings unveil special molecular features, carcinogenesis, and prognosis of sporadic SCRC. Strategies for targeted therapy and immunotherapy should be optimized accordingly.

Keywords: heterogeneity; molecular landscape; neutral evolution; synchronous colorectal cancer; whole-exome sequencing.

Graphical abstract

Figure 1

Genomic landscapes (A) The SNVs of the top 30 genes and the CNVs of driver genes with frequencies higher than 5% are displayed. Each column corresponds to one patient. The top graph shows mutation numbers. The right graph indicates the relative frequencies of distribution in paired samples from the same patient of a specific gene. Samples are ordered by case number from left to right and location from distal (DT) to proximal (PX) of the colon (from P1 to P51). (B) Mutational frequencies of top 30 selected driver genes in SCRC. (C) Three mutation signatures in SCRC are identified by whole-exome sequencing. The x axis represents the 96 combinations of trinucleotide motifs, and the y axis indicates the relative contribution to the detected signature. Abbreviations: SNV, single-nucleotide variant; CNV, copy-number variation; SCRC, synchronous colorectal cancer.

Figure 2

Molecular features of SCRC (A) The proportions of tumor mutation burden and microsatellite status in SCRC. (B) Venn diagram illustrating the genomic characteristics sharing status in SCRC samples. (C) Distributions of microsatellite status among different lesions of the colon. (D and E) Boxplots exhibit the distribution and comparison of the weighted genome integrity index (wGII) and mutant-allele tumor heterogeneity (MATH) in SCRC by anatomical region. Abbreviations: SCRC, synchronous colorectal cancer; TMB, tumor mutation burden; MSI, microsatellite instability; MSS, microsatellite stability.

Figure 3

Comparison of somatic alterations and clone compositions between paired tumors (A) Percentage of somatic non-silent mutations that are shared by paired tumors or are unique to one of them. (B) Cancer cell fraction of putative driver alterations that are shared by paired tumors. Only recurrent mutated genes are labeled on the plot. (C) Brief description of a scheme to estimate the origin between paired samples. (D) Pie chart displays the proportion of cases with genetically heterogeneous tumors in SCRC. Abbreviations: SCRC, synchronous colorectal cancer; DT, tumors located more distal to the other tumor; PX, tumors located more proximal to the other tumor.

Figure 4

Comparison between SCRC cohort and solitary CRC from TCGA cohort (A) Distribution and comparison of log10-transformed TMB between SCRC and solitary CRC. Horizontal bars indicate median values, boxes represent the interquartile range, and the whiskers indicate values within 1.5 times the interquartile range. (B and C) Frequencies of mutant genes and pathways in SCRC and solitary CRC. p values are for the comparisons of mutation frequencies between SCRC and solitary CRC. Abbreviations: SCRC, synchronous colorectal cancer; CRC, colorectal cancer; TCGA, The Cancer Genome Atlas; TSG, tumor-suppressor gene; OG, oncogene; TMB, tumor mutation burden.

Figure 5

Neutral evolutionary patterns in SCRC (A) The samples in this cohort are taken as examples to display the model’s pattern. The tumor predicted as neutral by the model if the cumulative distribution M(f) of subclonal mutations was found to be linear with 1/f (R² ≥ 0.98) and non-neutral otherwise (R² < 0.98). (B) The distribution and comparison of MATH by evolution model in SCRC. (C) Pie chart of the evolutionary pattern of paired samples from the same patient. (D) Kaplan-Meier analysis of OS and PFS by the evolutionary pattern from time of diagnosis of SCRC. p values of the analyses by the log-rank test are shown. Abbreviations: SCRC, synchronous colorectal cancer; OS, overall survival; PFS, progression-free survival.