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Colon Cancer

Author/Editor: Tilda Barliya PhD

Word Cloud By Danielle Smolyar

Colorectal cancer is the third most common type of cancer diagnosed in the United States and is the third most common cause of cancer-related death. The majority of cases are sporadic, with hereditary colon cancer contributing up to 15% of all colon cancer diagnoses. Treatment consists of surgery for early-stage disease and the combination of surgery and adjuvant chemotherapy for advanced-stage disease. Management of metastatic disease has evolved from primary chemotherapeutic treatment to include resection of single liver and lung metastases in addition to resection of the primary disease and chemotherapy (1-4).

Courtesy WebMD site

In the United States, colorectal cancer (CRC) is the third most common type of cancer diagnosed and the third most common cause of cancer-related death in men and women. In 2010, an estimated 102,900 new cases of colon cancer were diagnosed (49,470 male, 53,430 female) and 51,370 patients (26,580 male, 24,790 female) died from CRC. The death rate from colon cancer decreased over the preceding decade, from 30.77 per 100,000 people to 20.5 per 100,000 people. The lifetime risk of developing colon cancer in industrialized nations is 5% and is stable or decreasing. In contrast, the incidence in developing countries continues to rise, hypothesized to be due to increased exposure to risk factors. It has been estimated that 1.5 million people in the United States will be living with CRC by 2020.The financial burden of caring for this population is significant: $4.5 to $9.6 billion per year.

Colon Cancer is divided into 5 types:

1. Sporadic: 60-85%
2. Familial: 10-30%
3. Hereditary non-Polyposis Colon Cancer (HNPCC): 5%
4. Familial Adenomatous Polyposis (FAP): 1%
5. Autosomal Dominant Inheritance

The molecular defects are of two types:

• alterations that lead to novel or increased function of oncogenes
• alterations that lead to loss of function of tumor-suppressor genes (TSGs)

Multiple genes are associated with the initiation and progression of the different syndromes of colon cancer and are summarized by Fearon ER in Table 1 (6):

Table 1  Genetics of inherited colorectal tumor syndromes^a

Syndrome	Common features	Gene defect(s)
FAP	Multiple adenomatous polyps (>100) and carcinomas of the colon and rectum; duodenal polyps and carcinomas; fundic gland polyps in the stomach; congenital hypertrophy of retinal pigment epithelium	APC (>90%)
Gardner syndrome	Same as FAP; also, desmoid tumors and mandibular osteomas	APC
Turcot’s syndrome	Polyposis and colorectal cancer with brain tumors (medulloblastomas); colorectal cancer and brain tumors (glioblastoma)	APC
		MLH1, PMS2
Attenuated adenomatous polyposis coli	Fewer than 100 polyps, although marked variation in polyp number (from 5 to >1,000 polyps) observed in mutation carriers within a single family	APC(predominantly 5′ mutations)
Hereditary nonpolyposis colorectal cancer	Colorectal cancer without extensive polyposis; other cancers include endometrial, ovarian and stomach cancer, and occasionally urothelial, hepatobiliary, and brain tumors	MSH2
		MLH1
		PMS2
		GTBP, MSH6
Peutz-Jeghers syndrome	Hamartomatous polyps throughout the GI tract; mucocutaneous pigmentation; increased risk of GI and non-GI cancers	LKB1, STK11(30–70%)
Cowden disease	Multiple hamartomas involving breast, thyroid, skin, central nervous system, and GI tract; increased risk of breast, uterus, and thyroid cancers; risk of GI cancer unclear	PTEN (85%)
Juvenile polyposis syndrome	Multiple hamartomatous/juvenile polyps with predominance in colon and stomach; variable increase in colorectal and stomach cancer risk; facial changes	DPC4 (15%)
		BMPR1a(25%)
		PTEN (5%)
MYH-associated polyposis	Multiple adenomatous GI polyps, autosomal recessive basis; colon polyps often have somatic KRAS mutations	MYH

Essentially all of the genes discussed above are conclusively implicated in subsets of CRC due to specific somatic defects that either activate or inactivate gene and protein function. It is hypothesized that essentially any gene with dysregulated expression in CRC—either increased or decreased expression—may have a functionally significant role as an oncogene or a TSG, respectively. The aggregate data on the mutations and function of any given gene must be carefully evaluated to establish whether the gene truly contributes to CRC pathogenesis and whether it should be designated as an oncogene or a TSG (5,6).

The first proposed genetic model of CRC assumed that most CRCs arise from preexisting adenomatous lesions and that the accumulation of multiple gene defects is required for CRCs.

Benign GI tumors are a varied group, but localized lesions that project above the surrounding mucosa are commonly termed polyps. In humans, most colorectal polyps, particularly small polyps less than 5 mm in size, are hyperplastic (6). Most data indicate that hyperplastic polyps are not a major precursor to CRC; rather, the adenomatous polyp, or adenoma, is probably the important precursor lesion (7).

” Adenomas arise from glandular epithelium and are characterized by dysplastic morphology and altered differentiation of the epithelial cells in the lesion. The prevalence of adenomas in the United States is approximately 25% by age 50 and approximately 50% by age 70 (8)”. Only a fraction of adenomas progress to cancer, and progression probably occurs over years to decades. Individuals affected by syndromes that strongly predispose to adenomas, such as FAP, invariably develop CRCs by the third to fifth decade of life if their colons are not removed”.

A more recent and modified version of the genetic model postulate that each gene defect described in the model occurs at high frequency only at particular stages of tumor development. This observation is the basis for assigning a relative order to the defects in a multistep pathway.

Colon Cancer and clinical Trails:

Mutations in the KRAS proto-oncogene are found in 40-45% of patients with CRC and occur mainly in exon 2 (codon 12 and 13) and to a lesser extent in exon 3 (codon 61) and exon 4 (codon 146). A number of studies have evaluated a potential prognostic role of KRAS  in clinical practice for the treatment of colorectal cancer. However, clinical study design, reproducibility, interpretation and reporting of the clinical data remain important challenges.

Laurent-Puig’s group was the first to show the negative predictive value of KRAS mutations for response to the EGFR monoclonal antibody (mAb) cetuximab (11, 12, 13). Ever since then, a number of large phase II-III randomized studies have confirmed the negative predictive value of KRAS mutations for response to cetuximab and panitumumab treatment.

The role of KRAS mutations in predicting response to other therapies remains unclear. A subset analysis of patients treated in the phase III study of bevacizumab plus IFL (irinotecan, bolus 5-FU, and folinic acid) versus IFL showed that the clinical benefit of bevacizumab is independent of KRAS mutational status (11, 14).

“The KRAS biomarker story is unique in several ways. It represents the first biomarker integrated into clinical practice in CRC“.

The high prevalence of KRAS mutations in CRC and its strong negative predictive value for EGFR mAb therapies, has led to its rapid acceptance as a valuable biomarker. The EMEA, FDA and ASCO47 now recommend that all patients with metastatic CRC who are candidates for anti-EGFR mAb therapy should be tested for KRAS mutations and, if a KRAS mutation in codon 12 or 13 is detected, then patients should not receive anti-EGFR antibody therapy.

More so, Data from the PETACC-3 trial, presented at ASCO 2010, have shown that KRAS and BRAF mutant CRC tumors induce different gene-expression profiles, further reiterating that these tumors have a distinct underlying biology. Despite intensive progress in the field of genomic research, none of these genomic markers are used routinely in clinical trials.  Only, nowadays, trials are starting to use specific gene-pathway” target in CRC clinical trials.

Samuel Constant et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Summary:

Early studies are underway to understand the role of DNA methylation, chromatin modification, changes in the patterns of mRNA and noncoding RNA expression, and changes in protein expression and posttranslational modification. However,  we do not yet have an indepth and comprehensive understanding of the pathogenesis of the biologically and clinically distinct subsets of CRC. Careful design of clinical trials end points and validation of the genes as potential prognostic markers will allow a better outcome for these patients.

Ref:

1. Sarah Popek, MD, and Vassiliki Liana Tsikitis, MD. Colorectal Cancer: A Review. OncLive  November 10, 2011. http://www.onclive.com/publications/contemporary-oncology/2011/fall-2011/Colorectal-Cancer-A-Review

x. Martin Hefti.,  H.Maximilian Mehdorn., Ina Albert and Lutz Dörner. Fluorescence-Guided Surgery for Malignant Glioma: A Review on Aminolevulinic Acid Induced Protoporphyrin IX Photodynamic Diagnostic in Brain Tumors.  Current Medical Imaging Reviews, 2010, 6, 1-5. http://www.hirslanden.ch/content/global/en/startseite/gesundheit_medizin/mediathek_bibliothek/fachartikel/verschiedenes/fluorescence_guidedsurgeryformalignantglioma/_jcr_content/download/file.res/FluorescenceGuidedSurgeryforMalignantGlioma.pdf

2. Oguz Akin, Sandra B. Brennan., D. David Dershaw., Michelle S. Ginsberg., Marc J. Gollub., Heiko Sch€oder., David M. Panicek, and Hedvig Hricak. Advances in Oncologic Imaging: Update on 5 Common Cancers. CA CANCER J CLIN 2012;62:364–393. http://onlinelibrary.wiley.com/doi/10.3322/caac.21156/pdf

3. O’Donnell, Kevin et al. Nanoparticulate systems for oral drug delivery to the colon. International Journal of Nanotechnology, 2010, 8, 1/2, 4-20. “Colonic Navigation: Nanotechnology Helps Deliver Drugs to Intestinal Target”. http://www.sciencedaily.com/releases/2010/11/101104154553.htm

4. Perumal V. Molecular Therapy and Nanocarrier Based Drug Delivery to Colon Cancer: Targeted Molecular Therapy (AEE788 and Celecoxib) and Drug Delivery (Celecoxib) To Colon Cancer. http://www.amazon.com/Molecular-Therapy-Nanocarrier-Delivery-Cancer/dp/3659162558

5. Xiaoyun Liao, Paul Lochhead, Reiko Nishihara, Teppei Morikawa, Aya Kuchiba, Mai Yamauchi, Yu Imamura, Zhi Rong Qian, Yoshifumi Baba, Kaori Shima, Ruifang Sun, Katsuhiko Nosho, Jeffrey A. Meyerhardt, Edward Giovannucci, Charles S. Fuchs, Andrew T. Chan, Shuji Ogino. Aspirin Use, TumorPIK3CAMutation, and Colorectal-Cancer Survival. New England Journal of Medicine, 2012; 367 (17): 1596 DOI:10.1056/NEJMoa1207756. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532946/

Gene Mutation Identifies Colorectal Cancer Patients Who Live Longer With Aspirin Therapy. http://www.sciencedaily.com/releases/2012/10/121024175357.htm

6. Fearon ER. Molecular Genetics of Colorectal Cancer. Annual Review of Pathology: Mechanisms of Disease 2011; 6: 479-507.http://www.annualreviews.org/doi/pdf/10.1146/annurev-pathol-011110-130235

7.  Jass JR. 2007. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Hisopathology 50:113–130. http://www.amedeoprize.com/ap/pdf/histopathology.pdf

8.  Rex DK, Lehman GA, Ulbright TM, Smith JJ, Pound DC, et al.  Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am. J. Gastroenterol 1993. 88:825–831.http://www.ncbi.nlm.nih.gov/pubmed/8503374

9. Kerber RA, Neklason DW, Samowitz WS, Burt RW. Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Fam. Cancer 2005; 4:239–44. http://www.ncbi.nlm.nih.gov/pubmed/16136384

10. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996: 87:159–170. http://users.ugent.be/~fspelema/les%204-5%20HMG/kinzler%20clon.pdf

11. Sandra Van Schaeybroeck, Wendy L. Allen, Richard C. Turkington & Patrick G. Johnston. Implementing prognostic and predictive biomarkers in CRC clinical trials.(colorectal cancer)(Clinical report). Nature Reviews Clinical Oncology 2011: 8; 222-232. http://www.nature.com/nrclinonc/journal/v8/n4/abs/nrclinonc.2011.15.html

12. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66 2006: 3992-3995. http://hwmaint.cancerres.aacrjournals.org/cgi/content/full/66/8/3992

13. Lievre, A. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008: 26, 374-379. http://jco.ascopubs.org/content/26/3/374.full.pdf

14. Hurwitz, H. I., Yi, J., Ince, W., Novotny, W. F. & Rosen, O. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist  2009: 14, 22-28. http://theoncologist.alphamedpress.org/content/14/1/22.full

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Aviva Lev-Ari, PhD, RN. Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. http://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. http://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.D. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. http://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.D. In Focus: Targeting of Cancer Stem Cells. http://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. http://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. http://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. http://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

Other posts by the group: Please see http://pharmaceuticalintelligence.com/?s=colon+cancer