Chapter Eight - Field carcinogenesis for risk stratification of colorectal cancer

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Abstract

Colorectal cancer (CRC) is characterized by genetic-environmental interplay leading to diffuse changes in the entire colonic mucosa (field carcinogenesis or field of injury) and to a pro-neoplastic genetic/epigenetic/physiological milieu. The clinical consequences are increased risk of synchronous and metachronous neoplasia. Factors such as genetics, race, ethnicity, age, and socioeconomic status are thought to influence neoplasia development. Here, we explore the potential improvement to CRC screening through exploiting field carcinogenesis, with particular focus on racial disparities and chemoprevention strategies. Also, we discuss future directions for field carcinogenesis/risk stratification using molecular and novel biophotonic techniques for personalized CRC screening.

Section snippets

Field carcinogenesis and colorectal cancer risk

The concept of field effect (a.k.a. field defect, field carcinogenesis, field of injury) has a myriad of definitions and has evolved over time. It was first coined by Slaughter in 1953 when he noted the high rate of metachronous cancers in patients whose oral cancers were successfully resected (Slaughter, Southwick, & Smejkal, 1953). The molecular basis for this has been supported by observations from Sidransky et al. that p53 mutations occur diffusely in the microscopically normal mucosa of

Biomarkers of field carcinogenesis

In order to exploit field carcinogenesis for clinical use, marker selection is critical. The nature of the markers varies, and includes biochemical, immunohistochemical, cellular, genomic, epigenetic, and microvascular/microarchitectural alterations. Here we will focus on the evidence for various schemata that capture metabolic and optically detectable markers of field carcinogenesis (Backman & Roy, 2011).

Metabolic markers

Metabolic changes are considered one of the hallmarks of malignant transformation (Hanahan & Weinberg, 2011) and can provide the requisite anabolic underpinnings for the hyperproliferative mucosa noted in field carcinogenesis. With regard to potential clinical correlates, metabolic diseases are well-established to predispose to colonic neoplasia. For instance, a number of studies have linked obesity to ~ 30%–70% increased risk of CRC, albeit greater in men than women (Bardou, Barkun, & Martel,

Current clinical applications

By definition, field carcinogenesis is a determinant of progression to CRC, and increases risk of both synchronous and metachronous neoplasia. Clinically, this is already well-established and acts as the basis of practice for CRC screening and diagnosis. Examination of the distal colon alone with flexible sigmoidoscopy has been shown to decrease the risk of both distal and proximal cancers (Chung, Hakim, Siddiqui, & Cash, 2020; Holme et al., 2017). Furthermore, current guidelines recommend

Flexible sigmoidoscopy (FS) and field carcinogenesis

FS epitomizes field carcinogenesis in that detection of polyps in the distal colon is well established to be a harbinger of lesions throughout the organ. FS examines the lower half of the large intestine, and requires no sedation and a more limited bowel preparation than other structural examinations. FS also has the capacity to remove polyps as for biopsy necessary.

In a systemic review, using the sigmoid-descending colon junction as the extent of examination, Lewis et al. noted an OR for

Colonoscopy: Post-polypectomy surveillance

Since colonoscopy entails visualization of the entire colon, at first pass one might not think field carcinogenesis is relevant. However, it is integral to management of patients in two scenarios: adenomas found at colonoscopy, and a completely negative colonoscopy.

Adenomatous polyps are marker of field carcinogenesis. The concept of condemned mucosa portends metachronous lesions. There is strong data supporting the notion that the severity of neoplasia mirrors the strength of field

Negative colonoscopy follow-up

The converse of using adenoma detection as a marker for the presence of a field effect, and thus more frequent follow-up, is the situation where no adenoma is detected. Does that indicate the lack of field carcinogenesis and hence a long-term projection of low risk? For instance, Singh and colleagues did an administrative review of a cohort of 35,975 patients from Manitoba with negative colonoscopy. The standardized incidence ratios (SIRs) of CRC in this cohort as compared to the general

Field carcinogenesis in inflammatory bowel disease (IBD)

CRC is one of the most feared complications of chronic inflammatory bowel disease (IBD). The prevalence has been decreasing with better medical therapies, but it is still believed to occur in ~ 18% for those with colitis for 30 years. The biology of CRC is quite distinct from sporadic disease from a molecular genetic perspective. Chronic inflammation is believed to induce oxidative stress leading to DNA damage, and resulting in activation of proto-oncogenes and inhibition of tumor suppressor

CRC racial disparities and field carcinogenesis

As discussed in depth in other chapters, there are important racial differences in CRC incidence and mortality. While there are a myriad of potential etiologies underlying such disparities, including access to care and concurrent risk factors (e.g., diabetes and obesity), there is evidence for at least some biological underpinnings, including mutational predilection (Guda et al., 2015). Field carcinogenesis may differ by race, based on interval cancer rates (i.e., cancers that occur after a

Optically detectable markers of field carcinogenesis

Biophotonics applies optical techniques to probing tissue structure. Various techniques have been applied in endoscopy, albeit the focus of most work has been on optical biopsy (i.e., ascertaining whether lesions are neoplastic or benign). There are a myriad of techniques that numerous groups have developed to examine the micro- and nano-structures within the cell and to quantify disturbances. The Backman lab has pioneered development of various technologies to probe different structural facets

Micro-circulation

There is an increase in pericryptal micro-circulation during colon carcinogenesis, termed early increase in blood supply (EIBS) (Wali et al., 2005). This reflects the increased energy demand during field carcinogenesis coupled with metabolic changes, such as those of the Warburg effect. PGS measurements have been corroborated with other techniques, including confocal endomicroscopy, Western blot analysis of hemoglobin in colonic mucosal scrapings, and immunohistochemical analysis of microvessel

PGS

EIBS was demonstrated to be increased in both the azoxymethane-treated rat and the MIN mouse (multiple intestinal neoplasia, the murine model of familial adenomatous polyposis) at timepoints that precede neoplasia. Indeed, at the earliest timepoint, the increased blood supply had a sensitivity of 94%, a specificity of 96%, and a positive predictive value of 96.8% for future neoplasia. This was followed up with a study of endoscopically normal mucosa from 37 patients, comparing those with no

LEBS

LEBS initially was developed with a table-top instrument on ex vivo tissue. This was validated in both the azoxymethane-treated rat and the MIN mouse. Pilot human studies (N = 63) centered on one parameter, spectral slope, which was shown to be altered in the microscopically normal mucosa in proximity to the adenomas (Roy et al., 2006). To investigate the potential clinical translatability of this approach, biopsies were obtained from the normal-appearing rectal mucosa of 219 patients undergoing

PWS

The clinical approach with PWS involves brushings of the rectum, done endoscopically or with an anoscope/cytological brush. These are applied to microscope slides and fixed. The PWS instrument, in conjunction with scanning brightfield components, allows targeting of the nucleus, supranuclear areas, cytoplasm etc.

The PWS parameter Ld was shown to be able to accurately distinguish the intestinal mucosa of MIN mice prior to tumorigenesis from age-matched wildtype mice (Subramanian et al., 2008).

Problems in implementing field carcinogenesis in clinical practice

Biologically, the concept of field carcinogenesis (field of injury) is robust and utilized clinically in some scenarios (e.g., post-polypectomy surveillance); however, there are potential caveats that need to be considered before there can be wider implementation for patient care. The major limitation is that it provides a probability of concurrent/future neoplasia, and does not definitely identify the lesion. The occurrence of neoplasia is a stochastic event requiring the inactivation of APC,

Chemoprevention via field carcinogenesis biomarkers assessed by biophotonics

Chemoprevention of colorectal neoplasia epitomizes field changes in that effective agents can suppress neoplasia throughout the colon. While there has been a myriad of agents that have been proven to prevent colon cancer, clinical implementation has been stymied by lack of intermediate biomarkers to both perform clinical validation and to personalize therapy (Umezawa et al., 2019). For clinical validation, the standard approach has been adenoma recurrence (Katona & Weiss, 2020). However, this

Conclusions/future potential

The role of field carcinogenesis in the development of colorectal neoplasia is biologically robust and clinically utilized. The evidence for field carcinogenesis in CRC is unequivocal, and there is a myriad of putative biomarkers that provide biological insights into the earliest events in colon carcinogenesis. While bench-to-bedside transition has been disappointing thus far, the adenoma remains a stalwart of clinical risk stratification (e.g., post-polypectomy surveillance or paradigms with

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