The hypermutated tumors, representing 16% of all CRCs, are deficient in the mismatch-repair (MMR)

mechanisms controlling the correction of errors that occur during DNA replication. The end result of

MMR deficiency is a form of genetic instability characterized by the accumulation of mutations

throughout the genome, primarily in repetitive sequences known as microsatellites; this is known as

microsatellite instability (MSI).29 The mutational burden ultimately provides these MSI tumors with

their malignant potential. Unlike CIN tumors, MSI tumors generally remain diploid or near-diploid.

They are less likely to have KRAS, TP53, SMAD4 mutations, and more likely to have BRAF and TGFBR2

mutations (Fig. 68-4). MSI can arise from either the germline inactivating mutations or the epigenetic

silencing of one of several MMR genes (MLH1, MLH3, MSH2, MSH3, and MSH6). Research into the

mechanisms of epigenetic silencing of MSI tumors has helped elucidate the CpG Island Methylator

Phenotype (CIMP), whereby the methylation of CpG sequences in the promoter region of MMR genes

(most commonly MLH1) leads to their transcriptional silencing.

The classification of CRC according to the type of genomic instability is clinically relevant. MSI

tumors tend to be preferentially right sided, have a solid or cribriform histologic pattern, contain large

number of tumor-infiltrating lymphocytes, are less responsive to fluoropyrimidine, and in general carry

a better prognosis, compared to CIN tumors.

The genomic instability that characterizes CRC is associated with alterations in a number of key

pathways; among others, the WNT, MAPK, PI3K, TGF-β and p53 pathways (Fig. 68-5). The WNT

signaling pathway contributes to the tightly regulated homeostasis of intestinal epithelial crypts, and its

alteration is considered an initiating event in colorectal carcinogenesis. The WNT signaling pathway is

altered in greater than 90% of both hypermutated and nonhypermutated CRCs. The most prevalent

alteration leading to dysregulation of the WNT pathway occurs through biallelic inactivation of the

tumor suppressor adenomatous polyposis coli (APC) gene.30 Patients with familial adenomatous

polyposis (FAP) have a germline mutation in one allele of the APC gene, and their risk of developing

CRC is virtually 100%. The WNT pathway is also commonly altered as a result of stabilizing mutations

of the CTNNB1 gene coding for β-catenin, a protein normally targeted for degradation by APC. The

accumulation of β-catenin as a result of APC loss or stabilizing CTNNB1 mutations leads to its

translocation to the nucleus, where it interacts with transcription factors of the TCF/LCF family, turning

them into transcriptional activators. The end result is an increase in the transcription of genes that are

normally important for stem cell renewal and differentiation but, when inappropriately expressed at

high levels, can cause cancer.

Figure 68-4. Most significantly mutated genes in hypermutated and nonhypermutated tumors. Blue bars represent genes identified

using the MutSig algorithm, and black bars represent genes identified by manual examination of sequence data. (From

Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. The Cancer Genome Atlas Network. Nature

2012;487(7407):330–337.)

Mutational inactivation of the TGF-β pathway, important in regulating cell growth arrest and

apoptosis, is a common event in CRC.31 In the majority of hypermutated tumors, the TGF-β gene is

inactivated by a frameshift mutation in a polyadenine repeat within the coding sequence. It can also be

inactivated by point mutation in the kinase domain. Downstream effectors of this pathway such as the

transcription factor SMAD4, and associated proteins SMAD2 and SMAD3, are also inactivated by

mutation or homozygous deletion of chromosomal segment 18q. Another member of this pathway,

deleted in CRC (DCC), is also commonly inactivated by deletion of chromosome 18q.

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Figure 68-5. Frequency of genetic changes leading to deregulation of recognized signaling pathways in CRC. Alterations are

defined as somatic mutations, homozygous deletions, high-level focal amplifications, and in some cases, significant up- or

downregulation of gene expression. Red/blue denote activation/inactivation, respectively. Bottom panel shows alterations across

samples in five main pathways (WNT, TGF-B, RTK/KRAS, PI3K, TP53, if at least one gene in the pathway is altered). nHM,

nonhypermutated; HM, hypermutated. (From Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. The

Cancer Genome Atlas Network. Nature 2012;487(7407):330–337.)

A common theme of the WNT and TGF-β signaling pathways is the increased activity of c-Myc, a

regulator gene that codes for a multifunctional transcription factor which plays a role in cell cycle

progression, apoptosis, and cellular transformation. c-Myc seems to play a central role in colorectal

carcinogenesis.32

The TP53 gene is a member of a pathway of regulators of cell cycle arrest and cell death in response

to a variety of genotoxic stresses. Mutations in the TP53 tumor suppressor gene occur in more than half

of nonhypermutated CRCs. In most tumors, both alleles of the gene are inactivated by a combination of

a mutation in one allele, and loss of the second allele by deletion of the chromosomal segment 17p. Loss

of the TP53 tumor suppressor gene is generally considered an early event that plays a role in the

transition from adenoma to invasive carcinoma.33 In hypermutated tumors, the TP53 pathway may be

attenuated by mutations in other genes, such as the proapoptotic BAX.

The MAPK pathway consists of a cascade of tightly coordinate kinases that work together to regulate

cell division and proliferation. KRAS, a protooncogene that becomes constitutively activated by

mutation, resulting in uncontrolled cell proliferation, is mutated in 37% of CRC. Interestingly, a number

of studies from model organisms reveal that KRAS mutation by itself is not sufficient to initiate

tumorigenesis; in order to have oncogenic potential it requires a previous APC mutation. The MAPK

pathway is the molecular pathway that has successfully been therapeutically targeted in CRC. Inhibition

of this pathway using antibodies against the epidermal growth factor receptor (EGFR) reduces

progression in wild-type KRAS/NRAS metastatic CRC.34 Activating mutations of BRAF, also an effector

member of the MAPK pathway downstream of KRAS, are seen in 13% of CRC. The BRAF mutation,

found almost exclusively in hypermutated tumors, has been associated with poor prognosis.

The PI3K/AKT/mTOR signaling pathway, with important roles in cell proliferation and apoptosis, is

abnormally activated in nearly half of all CRCs. Moreover, in the TCGA cohort, PI3K and RAS pathways

are simultaneously affected by mutations in one-third of all CRCs, suggesting that simultaneous

inhibition of both pathways may be required to achieve a therapeutic effect.35

The characterization of genome-level alterations in CRC has led to the identification of new subclassifications that share marked similarities across genomic structure, gene and protein expression, and

even the activity of the tumor microenvironment.36–39 While these sub-classifications continue to be

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resolved and studied, they have shown potential to prognosticate tumor behavior and oncologic

outcomes.40

The advances in genomic characterizations have revealed CRC to be a heterogeneous and complex

disease. While the patterns of genomic instability and alterations of signaling pathways are aligned with

specific phenotypic tumor characteristics, many tumors do not fit cleanly into any single category.

Rather, they may host elements of genomic instability and dysregulated signaling pathways that may

not be well characterized yet.

HISTOPATHOLOGY AND PROGRESSION

CRC is an adenocarcinoma arising from the epithelial lining of the large bowel. Some CRCs may

develop de novo, but most result from malignant transformation of adenomatous polyps. In the past,

only tubular and villous adenomas were considered to develop into invasive adenocarcinomas.

However, recent evidence suggests that serrated polyps can also develop into CRCs. Polyps arise from

normal mucosa, and gradually increase in size. Some polyp characteristics – size larger than 1 cm,

tubulovillous or villous histology, multiple occurrences – are associated with a high risk of malignant

transformation. Most screening programs are designed to recognize the presence of polyps, or early

malignant change in polyps or the surrounding mucosa.

HISTOPATHOLOGIC TYPES OF COLORECTAL CANCER

Table 68-2 Colorectal Cancer: Histopathologic Types

The majority of CRCs are typically adenocarcinomas that form glandular structures resembling the

normal colonic epithelium. However, there are several histologic types of adenocarcinoma (Table 68-2).

Colorectal adenocarcinomas are assigned to one of four histologic grades according to their histologic

resemblance to the normal colonic epithelium (Table 68-3). The histologic grade is associated with

oncologic outcome independent of other risk factors, including tumor staging.

CRC is locally invasive, potentially spreading through the full thickness of the bowel wall into

adjacent tissues. From the primary site, CRC often extends to the regional lymph nodes and to other

organs. CRC can metastasize to almost any organ, but the most common sites are the liver and lungs.

Approximately 20% to 34% of patients have metastases at the time of diagnosis, and another 30% of

those initially treated with curative intent will subsequently develop distant metastases. Other sites of

distant metastasis are the brain and bones, but these are unusual in the absence of liver metastases.

Patients may also develop peritoneal spread, with the formation of malignant ascites. The risk of nodal

metastasis increases with the depth of tumor invasion into the bowel wall, and the risk of distant

metastasis is higher for patients with nodal metastasis.

STAGING AND PROGNOSIS

The anatomical extent or stage of the tumor at the time of diagnosis is a key factor in deciding upon

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