c.1994delGL688XCRC, GC

this hyperplasia may predispose to the loss of heterozygosity (LOH) of APC. Indeed, K-ras mutation is expressed in the upper part of the crypt, where APC LOH takes also place (39). In the background of biallelic APC loss, K-ras mutation imposes a further obstacle in APC mt/mt cells to dedifferentiate, as they try to migrate towards the top of the crypt

These data suggest that some CRCs may be ‘born to be bad’, wherein invasive and even metastatic potential is specified early19,20.

However, CRC progression is not necessarily linear. Rather, we described a Big Bang model of tumor evolution, in which after transformation some CRCs grow as a single expansion populated by heterogeneous and effectively equally fit subclones, and from which most detectable intratumor heterogeneity arises early19.

Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells

Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

Our results suggest that many driver mutations in cancers with mismatch repair deficiencies may arise independently from, or prior to, loss of mismatch repair.

We found 13 significant associations arising between driver mutations and mutational signatures implicated in mismatch repair deficiency (signatures 6, 14, 20 and 26 [5, 9]; Table 2). These associations arise in stomach and colorectal adenocarcinoma and uterine corpus endometrial carcinoma, and they involve eight different driver mutations (Table 2). Interestingly, only three of these eight mutations occur in trinucleotide contexts that frequently appear in any of the mismatch repair deficiency signatures (Table 2).

Main Risk Factors Association with Proto-Oncogene Mutations in Colorectal Cancer

Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status

Mouse models of DNA mismatch repair in cancer research

Murine models of colorectal cancer

Before the advent of high-throughput sequencing, the discovery of Lynch Syndrome was a clear indication that the presence of passenger genetic events could indicate a DNA repair deficiency. Lynch syndrome, a cancer predisposition syndrome associated with an elevated risk of colon and endometrial cancers, is now known to be caused by germline mutations in the MMR pathway. MMR plays an important role in correcting insertion/deletion loops that occur during replication and are less likely to be caught by proof-reading domains of DNA replication polymerases, especially at microsatellites11. Detection of unstable microsatellites has been used to identify MMR-deficient tumors in colon and endometrial cancers for nearly two decades12. Recent pan-cancer extension of this type of analysis has identified low levels of MMR deficiencies in many other malignancies, some not previously thought to be associated with Lynch Syndrome13.

The highlight in the cross-talk between the Wnt/β-catenin and RAS-ERK pathways is the stability regulation of RAS by the Wnt/β-catenin signaling involving the GSK3β kinase mediated phosphorylaton of RAS.40

The CSC activation by mutant KRas with Apc loss is attributed strongly enhanced activation of β-catenin by its initial activation and its further activation by the stabilized oncogenic KRas by Apc loss followed by activation of the downstream RAF-MEK and ERK cascade (Fig. 5).

Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet remain largely uncharacterized. To gain a better understanding of their distribution and functional impacts, we leveraged the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7,500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, revealed a wide diversity of tissuespecific mutation profiles associated with gene expression levels and chromatin states. We found pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which were under positive selection and were highly enriched in many healthy tissues. These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis.

Genetic model of CRC. Classical adenoma-to-carcinoma sequence and the 2 main genetic instability pathways for colorectal tumorigenesis.

Recent studies of ERBB2 amplification and sequence mutations in colorectal cancer (CRC) suggest that HER2 is a therapy target in this disease,29-33 in addition to being a mechanism of resistance to epidermal growth factor receptor (EGFR)‐targeted therapies such as cetuximab and panitumumab.34-38

Driver mutations are recurrent in cancer because they experience positive selection. Consequently, the frequency that a particular driver is observed across cancers is a function both of the mutational likelihood of it occurring in the first place, and also the selective advantage that the mutation confers.

KRAS G12D (ACC > ATC) and KRAS G13D (GCC > GTC) were associated with MMR signatures in uterine carcinoma and stomach cancer, respectively (Fig. 2d).

Neither is BRAF V600E (GTG > GAG) explained by the dominant MMR-linked signature 6 in colorectal cancer.