结直肠癌的基因组特征与五类预后分型

Fig. 1 | Somatic mutation analysis of 1,063 CRC genomes identifies 96 driver genes. Somatic mutations were called (Methods) and significantly mutated genes were identified using dNdScv. a, The 96 genes mutated at a significant level in this cohort. The association of driver genes with survival (HR) is shown for HM and nHM tumours (multivariable Cox regression). The association of driver genes with clinical and genomic features is shown by the proportion of tumours affected (Fisher’s exact test). *FDR-adjusted P < 0.05. The mutation type and prevalence is indicated on the right, including a description of the affected pathway. Colour keys for HR for OS and RFS, and for genomic feature proportions are shown on the far right. Genes that were not previously designated as drivers in CRC (orange) or in any cancer type (blue) are indicated. b, The prevalence of total (blue) and non-synonymous (red) mutations in each tumour. Cut-offs for HM and nHM are indicated (grey line). The clinical features and mutation status for selected genes are shown at the bottom. Mutations that are considered to be drivers are either probably oncogenic mutations annotated by OncoKB or hotspots catalogued by Cancer Hotspots. c, DNA damage response (DDR) gene mutations in the 15 out of 21 HM tumour cases that were MSS. Not all DNA damage response genes included here can be interpreted as the direct cause of the high TMB in these MSS samples. Top, the total non-synonymous mutation counts for each sample are coloured by the affected oncogenic pathways. ADENOCA, adenocarcinoma; BER, base excision repair; HRR, homologous recombination repair; MMR, mismatch repair.

Fig. 2 | Structural variation and relative timing of somatic events in CRC. a, Gene CNVs in driver genes displayed by type: LOH (green), deletion (yellow) and amplification (red). The bar height is proportional to the fraction of tumours with respective alteration. The 91 autosomal driver genes are indicated as oncogenes (O; purple), tumour suppressor genes (S; orange), both (S, O; red) or genes with an unknown role (black), and are displayed by genomic location. b, The SV landscape for deletions, inversions, tandem duplications and translocations displayed by clinical, genomic and transcriptomic features. The boxes represent the interquartile ranges (IQRs) between the first and third quartiles, the centre line represents the median, and the whiskers extend to 1.5× the IQR from the top and bottom of the box. Statistical analysis was performed using two-sided Wilcoxon rank-sum tests; *FDR-adjusted P < 0.05, **FDR-adjusted P < 0.01, ***FDR-adjusted P < 0.001, ****FDR-adjusted P < 0.0001. c, The prevalence and relative timing of driver gene mutations and SVs in 801 nHM CRC tumours by PhylogicNDT. Early/clonal (green), intermediate (black) and late/subclonal (purple) alterations are indicated. WGD, whole-genome duplication.

Fig. 3 | Integrative analysis of somatic alterations and gene expression levels in CRC signalling pathways. The frequencies of somatic alterations, including mutations and copy-number (CNV) loss and gain for each gene in nHM and HM tumours. Red (log2[fold change (FC)] > 0) and blue (log2[FC] < 0) colour intensities represent the log-transformed FC between mutated and wild-type tumours by type of somatic alteration (mutation, CNV gain and CNV loss for nHM and HM samples). Somatic alteration frequencies are indicated by the black line in each column. Black dots show gene expression changes with FDR-adjusted P < 0.05 (two-sided Wilcoxon rank-sum test). Driver genes are marked by orange borders.

Fig. 4 | Refined prognostic subtypes derived from 1,063 CRC transcriptomes. The characteristics of the five distinct CRPSs obtained from unsupervised classification of tumour transcriptome data. a, Comparison of CRPS to the CMSs for the same dataset. The proportion of samples assigned to each subtype is shown as the percentage of the total number of tumours. The main molecular and clinical characteristics for each CRPS and CMS subgroup are indicated. b, Transcriptomic characteristics of 1,063 samples according to their CRPS classification. Prognostic focal CNV cytobands that are differentially altered in CRPS are indicated by asterisks (P < 0.05, multivariable Cox regression in nHM tumours). c, Kaplan–Meier survival curves (log-rank test) for overall (stages I–IV) and recurrence-free (stages I–III) survival in CRPS (top) and CMS (bottom) groups. d, Kaplan–Meier survival curves (log-rank test) for CMS4 samples allocated to CRPS2 and CMS4 samples allocated to the CRPS4 group. Adjusted HR (HRadj) and P values (Padj) or HR and P values were calculated using multivariable Cox regression with or without adjustment for tumour stage. CIN, chromosomal instability.

Table 1 | Prognostic genomic features by hypermutation status Feature nHM HM Longer survival Shorter survival Longer survival Shorter survival Coding driver gene mutation APCOS,RFS ARHGAP5OS,RFS ARHGAP5RFS BCL9OS SIN3AOS ARID2OS RNF43RFS PCBP1RFS BRAF OS,RFS TGFBR2RFS TRPS1OS RNF43OS,RFS Mitochondrial gene mutation MT-CYBOS,RFS − − − Non-coding driver gene mutation − ID2OS − − HS3ST1OS DAPK1RFS CNV +8p11.1OS −4q34.1OS − −3p21.31RFS +20q11.1OS,RFS −8p23.1OS −4q22.1RFS +20q11.21OS −11p15.5RFS −11p15.5OS,RFS +20q13.12OS −12q24.33RFS −15q26.3RFS +20q13.33OS −16p13.3RFS +19q11OS −17p12RFS −17p13.3RFS −17q12OS −17q21.2OS −17q21.31OS −17q25.3OS,RFS −21p12OS SV − SMAD4RFS − − TCF7L2OS,RFS Mutational signature − − SBS44OS − Prognostic features identified by multivariable Cox with adjustment for tumour site, pretreatment status, tumour stage, age group and tumour grade. OS, overall survival for stages I–IV. RFS, recurrence-free survival for stages I–III.