(a) The enrichment of canonical ‘core’ CRC
driver genes (APC, KRAS, TP53
or SMAD4; A, K, T or S) plus
recurrent mutations in candidate drivers (AMER1, ATM, BRAF, PIK3CA,
PTPRT or TCF7L2) identified in the mCRC cohort was
evaluated in an independent cohort of 2,751 CRC patients. The combined barplots
(left) illustrate the overall frequency of the ‘core’ module alone
or with an additional candidate driver (‘X’) in early stage versus
metastatic CRCs. Individual barplots indicate the frequency of specific
‘modules’. Q-values are based on two-sided Fisher’s exact
tests with Benjamini–Hochberg adjustment. (b) Three stages
of CRC progression are outlined: pre-malignancy (between initiation and
transformation), early-stage (between transformation and dissemination) and
late-stage (after dissemination). A set of potential interventions to prevent
cancer mortality targets each stage: for pre-malignant lesions, resection (after
detection via colonoscopy or possibly cell free DNA; cfDNA); for early-stage
CRC, surgical resection and possibly adjuvant chemotherapy; and for late-stage
CRC, chemotherapy and/or targeted/immune therapies. Given the high rate (80%
here) of early dissemination, prior to clinical detectability of the early-stage
CRC, detection and resection of pre-malignant lesions will have the greatest
impact on preventing cancer mortality. For tumors that undergo dissemination
prior to clinical detectability, surgical resection alone, even of a small
tumor, cannot prevent metastasis. Once the early-stage tumor is discovered,
newly defined metastatic modules (panel a) may inform patient stratification to
aid the directed use of adjuvant chemotherapy.