Colorectal Cancer

  • Diagnosis
  • Screening
  • Monitoring
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Colorectal bleeding
  • Family history of colorectal cancer (CRC)
  • Clinical symptoms consistent with genetic/hereditary CRC (eg, MUTYH-associated polyposis (MAP), familial adenomatous polyposis (FAP), Turcot syndrome, Gardner syndrome)

Histology

  • All polyps removed should have histologic examination
  • Tissue is gold standard for tumor classification and further testing
    • KRAS, NRAS, BRAF, PIK3CA, PTEN  genes for prognostication and therapy decisions
      • PTEN by IHC is adequate testing
    • Microsatellite instability (MSI)
    • Mismatch repair (MMR) genes
  • Immunohistochemistry (IHC) – identifies MMR genes to guide MMR gene mutation testing
    • All tumors should be tested – ~15% of sporadic CRC will have MSI
    • MLH1, MSH2, MSH6, PMS2 – MMR genes to test based on IHC results

Genetic Testing

  • MMR genes – should be considered for patients with newly diagnosed CRC
    • Presence confirms Lynch syndrome
  • Gene testing for other more rare syndromes should be based on clinical presentation and family history
    • APC gene – FAP or attenuated FAP
    • MUTYH gene – MAP
    • Peutz-Jeghers syndrome
    • Serrated polyposis syndrome

Prognosis

  • MMR-deficient tumors – generally more favorable prognosis
  • Chromosomal alterations in 8p, 17p, 18p – associated with poor prognosis
  • Serum markers
    • Carcinoembryonic antigen (CEA) – measure prior to surgery (ASCO, 2006)
    • Other potential but not validated serum markers – carbohydrate antigen (CA) 19-9, CA242, circulating tumor cells (CTC), and tissue inhibitor of metalloproteinase-1 (TIMP-1)
      • CTC – independent predictor of progression-free and overall survival

Differential Diagnosis

  • Direct evidence from clinical trials concludes that fecal occult blood testing and flexible sigmoidoscopy reduces mortality from colorectal cancer (CRC); however, National Comprehensive Cancer Network recommends colonoscopy as the preferred screening method (NCCN, 2014)
  • Fecal occult blood testing
    • 50% of confirmed colon cancer cases have a negative fecal occult blood test (FOBT)
      • If patient is at risk, consider sigmoidoscopy or colonoscopy even in the presence of a negative FOBT
    • Positive FOBT mandates further evaluation (eg, colonoscopy)
  • Flexible sigmoidoscopy/colonoscopy – negative result does not rule out CRC
    • 90% sensitivity for lesions ≥10 mm
  • Septin 9
    • Biomarker for presence of CRC – high negative predictive values
    • Indicated for individuals ≥50 years who have an average risk and no family history of CRC
    • Not recommended for individuals with
      • History of previous CRC
      • Above-average risk (eg, family history of early onset CRC, hereditary CRC)
      • Previous polyp removal
    • Not intended as substitute for colonoscopy – may be useful as a complement to colonoscopy or for those who are unwilling or unable to have a colonoscopy (Choosing Wisely: 5 Things Physicians and Patients Should Question, American Society of Clinical Pathology, 2015)
      • Patients with elevated level should undergo colonoscopy to rule out CRC
    • Has been shown to detect cancers in cecum, ascending colon, transverse colon, splenic flexure, descending colon, sigmoid, recto-sigmoid junction, and rectum
  • Serum carcinoembryonic antigen (CEA)
    • Elevated postoperative titer predicts tumor recurrence
    • Preoperative and postoperative monitoring for changes in concentration
      • Stage II or III tumors – measure every 3 months post operation, continuing for 3 years
    • Patient with metastatic disease – monitoring may help evaluate treatment response
  • Serum circulating tumor cell count (CTC) – in metastatic tumors, monitor disease progression and response to therapy
  • Others
    • Serum CA 19-9
    • Deletion 18q – not enough data to recommend use
    • 9q22.2-31.2 – promising new marker for hereditary colorectal cancers
  • UGT1A1 genotyping
    • Uridine diphosphate glucuronosyl transferase (UGT1A1) is responsible for clearance of irinotecan, a camptothecin analogue used in treatment of advanced colon cancer
    • Decreased gene expression may lead to drug toxicity (development of severe neutropenia)
      • Two gene variants responsible for 98-99% of genotypes in the Caucasian population – *1  and *28 (repeat TA sequence)
    • Routine reduction of dose in *28 homozygous is not recommended (Evaluation of Genomic Applications in Practice Working Group, 2009), but may identify patients at risk for adverse events and in need of closer monitoring
      • Selective genotyping based on patient preferences and predicted dosing
        • Higher doses associated with increased risk for certain genotypes that may not occur with lower dosing
        • Patients homozygous for *1 may tolerate aggressive treatment better than patients with the *28 variant
        • Patients homozygous for *28 may require a dose reduction to minimize dose-related adverse events
  • 5-fluorouracil (5-FU) sensitivity – genotyping of DYPD and TYMS
    • 5-FU is a fluoropyrimidine drug used in the treatment of colorectal cancer and other solid tumors
    • Pharmacogenetic variations in genes such as DPYD and TYMS may contribute to risk of toxicity or altered therapeutic benefits
      • DPYD or TYMS mutation detected – most mutations are associated with increased risk for 5-FU toxicity
        • Alternative chemotherapeutic agents, therapeutic drug monitoring, altered 5-FU doses, or increased surveillance for adverse drug reactions may be indicated

Colorectal cancer (CRC) is the third most common form of cancer in the U.S. It can be roughly divided into sporadic and hereditary types.

Epidemiology

  • Incidence – 43.7/100,000 (2011 U.S. SEER data)
    • Sporadic – most common form (~80%)
    • Most common hereditary CRCs
      • Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome – accounts for 2-4% of CRC cases in the U.S. (NCCN, 2014)
      • Familial adenomatous polyposis (FAP) – occurs in 1/10,000 live births
        • <1% of total CRC
      • MUTYH (formerly MYH)-associated polyposis (MAP) – rare
      • Others
        • Cowden syndrome (multiple hamartoma syndrome)
        • Peutz-Jeghers syndrome (PJS) – 1/200,000
        • Juvenile polyposis syndrome (JPS) – 1/100,000
        • Hereditary diffuse gastric cancer
        • Serrated polyposis syndrome
  • Age
    • Sporadic – median is 70 years
    • Hereditary – usually <60 years
      • FAP – average is 39 years
  • Sex – M>F

Genetics

  • Sporadic
    • TP53 gene – mutated in ~75% of sporadic tumors
    • DCC gene – mutated in ~70% of CRCs
    • DNA mismatch repair (MMR) genes – mutation or modification found in 15% of sporadic tumors
    • Hyperplastic polyposis syndrome (HPS) – rarely inherited
  • Hereditary
    • >10-15% of all CRC associated with familial clustering
    • Lynch syndrome – associated with microsatellite instability (MSI) and MMR gene mutation/modification (eg, MLH1, MSH2, MSH6, PMS2)
    • FAP
      • APC gene mutations – autosomal dominant inheritance; 25% of cases are de novo
        • Classic FAP and attenuated FAP forms
        • Gardner syndrome
        • Turcot syndrome
    • MAP
      • Biallelic mutations in the MUTYH gene cause disease – autosomal recessive inheritance
      • Two MUTYH mutations, Y165C and G382D, account for 85% of MAP in Caucasians
    • PJS – STK11 gene mutations
    • JPS – SMAD4 or BMPR1A gene mutations

Risk Factors

  • Diet high in animal fats (Western diet)
  • Patients with metabolic syndrome
  • Inflammatory bowel disease (eg, Crohn disease, ulcerative colitis)
  • Adenoma/sessile serrated polyp (SSP)
  • First-degree relative with colorectal adenoma or invasive CRC
  • Ureterosigmoidostomy – carcinoma can develop ≥15 years post procedure

Pathophysiology

  • Most CRCs arise from adenomatous polyps
    • Villous adenomas transform into adenocarcinomas more frequently than tubular adenomas
    • Subset of adenocarcinomas develop from hyperplastic-appearing polyps, especially large, right-sided polyps
    • Adenocarcinoma arising in a polyp is considered malignant when it penetrates into the submucosa
  • Other less-common tumors can occur (lymphomas, endocrine, mesenchymal)

Clinical Presentation

  • Symptoms vary with tumor location – most are located in sigmoid colon and rectum
    • Cecum and ascending colon – tumors may be very large without causing obstruction
      • Anemia – a common presenting symptom
    • Descending and transverse colon – tumors tend to obstruct and cause annular lesions (apple core or napkin ring) with abdominal pain and bloating
    • Rectosigmoid – hematochezia, tenesmus, and narrowing of stool caliber
  • Sporadic tumors – usually single tumors
  • Inherited syndromes – tumors tend to develop at a younger age
    • Lynch syndrome – may have multiple tumors
    • FAP (classic)
      • Affected persons develop hundreds to thousands of colon polyps and subsequent CRC
        • Often present with multiple tumors
        • Mean age of onset is 39 years
        • Presence of ≥100 polyps is sufficient for clinical diagnosis (or <100 polyps at younger ages in a family with identified FAP)
      • Increased risk for malignancy – thyroid, medulloblastoma, hepatoblastoma, pancreas, gastric/duodenal
      • Possible additional findings
        • Osteomas – Gardner syndrome
        • Gastric and duodenal polyps
        • Dental anomalies
        • Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
        • CNS tumors – Turcot syndrome
    • FAP (attenuated)
      • 10-100 polyps (average is 30) – frequently right-sided distribution
      • Cancer appears at older age than classic FAP (mean age >50 years)
      • Risk of other cancers similar to classic FAP
      • Extraintestinal manifestations of classic FAP are rare
    • MAP
      • 10-100 polyps
      • Mean age of onset is >third decade
      • Often indistinguishable from attenuated FAP (may have similar extraintestinal manifestations)
    • PJS
    • JPS
      •  Juvenile polyps found mainly in colon
    • Serrated polyposis syndrome
      • Serrated polyps usually >10 mm

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Occult Blood, Fecal by Immunoassay 2007190
Method: Quantitative Immunoassay

Limitations

Less sensitive than colonoscopy

Septin 9 (SEPT9), Methylated DNA Detection by Real-Time PCR 2003243
Method: Polymerase Chain Reaction

Limitations

Lower sensitivity for detecting adenomas and stage 1 CRC (based on studies performed at ARUP Laboratories and other laboratories)

Not all individuals with CRC will have a positive result

Do not use as screening in patients with previous history of CRC or in patients with family history of early onset colorectal or hereditary CRC

Individuals with positive results should have follow-up colonoscopy

Mismatch Repair by Immunohistochemistry 0049302
Method: Qualitative Immunohistochemistry

Limitations

~10% of individuals with LS will have IHC tests which show normal staining of the MMR proteins

Since the correlation of MSI with IHC is not 100%, direct testing of MSI by PCR may be helpful

Microsatellite Instability (MSI), HNPCC/Lynch Syndrome, by PCR 0051740
Method: Polymerase Chain Reaction/Fragment Analysis

Limitations

15% of sporadic CRCs are also MSI-H

Preoperative chemoradiation of rectal cancer may complicate IHC interpretation and/or decrease tumor mass and make MSI testing difficult; evaluation of pretreatment biopsies will avoid this limitation

Colon Cancer Gene Panel, Somatic 2011616
Method: Mass Spectrometry

Limitations

Limit of detection – ~10% mutant alleles

Mutations outside of codons tested will not be detected

KRAS Mutation Detection with Reflex to BRAF Codon 600 Mutation Detection 2001932
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations

Limit of detection – 10% mutant alleles

Oncogenic mutations outside of codons tested will not be detected

A substantial portion of individuals with wild-type KRAS still fail to respond to anti-EGFR agents, implicating downstream mutations

KRAS Mutation Detection 0040248
Method: Polymerase Chain Reaction/Pyrosequencing

BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations

Limit of detection – 10% mutant alleles

Oncogenic mutations outside of codon tested will not be detected

NRAS Mutation Detection by Pyrosequencing 2003123
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations

Limit of detection – 10% mutant alleles

Oncogenic mutations outside of codons tested are not detected

Presence or absence of mutations does not guarantee a positive response to anti-EGFR therapies

PTEN by Immunohistochemistry 2004115
Method: Immunohistochemistry

PTEN with Interpretation by Immunohistochemistry 2007031
Method: Immunohistochemistry

PIK3CA Mutation Detection 2004510
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations

Limit of detection – 10% mutant alleles

Oncogenic mutations outside of codons tested will not be detected

Presence or absence of mutations does not guarantee a response or lack of response to anti-EGFR therapy

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Familial Adenomatous Polyposis Panel: (APC) Sequencing and Deletion/Duplication, (MUTYH) 2 Mutations 2004915
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations

APC gene

  • Deep intronic or regulatory region mutations will not be identified
  • Variants of uncertain significance may be detected
  • Breakpoints of large deletions/duplications will not be determined

Only two MUTYH gene mutations will be tested – Y165C and G382D

Rare diagnostic errors may occur due to primer- or probe-site mutations

Negative result does not rule out FAP, APC-associated polyposis, or MAP due to the possibility of an undetectable mutation in the specific gene(s) analyzed or a mutation in another gene

Familial Adenomatous Polyposis (APC) Deletion/Duplication 2004920
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Limitations

Deep intronic or regulatory region mutations will not be identified

Variants of uncertain significance may be detected

Breakpoints of large deletions/duplications will not be determined

MUTYH-Associated Polyposis (MUTYH) 2 Mutations 2004911
Method: Polymerase Chain Reaction/Sequencing

Limitations

Not detected – large deletions; deep intronic, regulatory region, or promoter mutations

Rare diagnostic errors may occur due to primer- or probe-site mutations

MUTYH gene variants of unknown significance may be detected

MUTYH-Associated Polyposis (MUTYH) Sequencing 2006191
Method: Polymerase Chain Reaction/Sequencing

Limitations

Not detected – large deletions; deep intronic, regulatory region, or promoter mutations

Rare diagnostic errors may occur due to primer- or probe-site mutations

MUTYH gene variants of unknown significance may be detected

MUTYH-Associated Polyposis (MUTYH) 2 Mutations with Reflex to Sequencing 2006307
Method: Polymerase Chain Reaction/Sequencing

Gastrointestinal Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 15 Genes  2010198
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Not determined or evaluated – mutations in genes not included on the panel; deep intronic and regulatory region mutations; breakpoints for large deletions/duplications; PMS2 gene (associated with Lynch syndrome) is not included on this panel

Sequence changes in EPCAM will not be evaluated

Deletions/duplications may not be detected in exon 1 in CDH1 and MSH2 genes; exons 4, 6, and 7 in STK11 gene; exon 8 in PTEN gene; exon 9 in BMPR1A gene

Individuals with hematological malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen

  • Testing on cultured fibroblasts or buccal specimen is required for accurate interpretation of test results

Lack of a detectable gene mutation does not exclude a diagnosis of hereditary GI cancer syndrome

Not all predisposing genes are analyzed

Carcinoembryonic Antigen 0080080
Method: Quantitative Electrochemiluminescent Immunoassay

Limitations

Not sensitive or specific enough for screening in the general population

Circulating Tumor Cell Count 0093399
Method: Immunomagnetic Separation/Immunofluorescent Stain/Computer Assisted Analysis

Limitations

CTC test is not as accurate as imaging in assessing whether a patient has progressive disease

Doxorubicin therapy patients – allow at least 7 days following administration of dose before testing

Not detected – CTCs that do not express EpCAM; CTCs that express EpCAM but not cytokeratins 8, 18, and 19

Additional Tests Available

HNPCC/Lynch Syndrome (MLH1) Sequencing and Deletion/Duplication 0051650
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Comments

Detects germline MLH1 mutations

Use in mismatch repair (MMR)-deficient carcinoma with suggestive IHC (loss of MLH1 and PMS2 protein), absence of BRAF codon 600 mutation, and normal MLH1 methylation studies

HNPCC/Lynch Syndrome (MSH2) Sequencing and Deletion/Duplication 0051654
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Comments

Detects germline MSH2 mutations

Use in MMR-deficient carcinoma with suggestive IHC (loss of MSH2 and MSH6 protein)

Detects large MSH2 deletions and EPCAM 3 prime deletions

HNPCC/Lynch Syndrome (MSH6) Sequencing and Deletion/Duplication 0051656
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Comments

Detects germline MSH6 mutations

Use in MMR-deficient carcinoma with suggestive IHC (isolated loss of MSH6 protein)

HNPCC/Lynch Syndrome (PMS2) Sequencing and Deletion/Duplication 0051737
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Comments

Detects germline PMS2 mutations

Use in MMR-deficient carcinoma with suggestive IHC (isolated loss of PMS2 protein)

HNPCC/Lynch Syndrome Deletion/Duplication 2001728
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Comments

Order if sequencing studies have been performed at another laboratory and no mutations were detected

BRAF Codon 600 Mutation Detection with Reflex to MLH1 Promoter Methylation 0051750
Method: Polymerase Chain Reaction/Pyrosequencing

Comments

Recommended reflex test for differentiating between LS and sporadic CRC in tumors showing loss of MLH1

Reflex pattern – if no BRAF mutation is detected, MLH1 promoter methylation is evaluated

5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 5 Mutations 2007228
Method: Polymerase Chain Reaction/Single Nucleotide Extensions/Fragment Analysis

Comments

Predicts toxicity and responsiveness of tumor to 5-FU therapy

Clinical sensitivity– estimated at 31% for the DPYD variants analyzed

Analytical sensitivity/specificity – 99%

Dihydropyrimidine Dehydrogenase (DPYD), 3 Mutations 2012166
Method: Polymerase Chain Reaction/Single Nucleotide Extensions/Fragment Analysis

Comments

Predicts risk of toxicity to 5-FU therapy due to impaired metabolism

Clinical sensitivity – ~31% for DPYD variants analyzed

Analytical sensitivity/specificity – 99%

UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping 0051332
Method: Polymerase Chain Reaction/Fragment Analysis

Comments

Dosage planning for individuals

  • Who will receive high-dose irinotecan (>150 mg/m2)
  • With personal or family history of sensitivity to irinotecan
  • Who have experienced neutropenia while receiving irinotecan

Confirm suspected diagnosis of Gilbert syndrome

Solid Tumor Mutation Panel by Next Generation Sequencing 2007991
Method: Massively Parallel Sequencing

Comments

Simultaneously evaluates mutations in 48 genes, including BRAF, KRAS, NRAS, PIK3CA

Predicts prognosis and therapeutic response in patients with solid tumor cancers

For a full list of the targeted regions of the above genes, click here

Familial Adenomatous Polyposis (APC) Sequencing 2004863
Method: Polymerase Chain Reaction/Sequencing

Comments

Acceptable diagnostic or predictive testing for FAP

Large APC gene deletions and duplications are not detected

Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes 2012032
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Comments

Preferred panel for confirming a diagnosis of a hereditary cancer with personal or family history consistent with features of more than once cancer syndrome

Refer to Additional Technical Information document for list of genes tested

Cancer Panel, Hereditary, Deletion/Duplication, 46 Genes 2010757
Method: Exonic Oligonucleotide-based CGH Microarray

Comments

Use to test known familial deletions/duplications in one of the 46 genes on the panel

Refer to Additional Technical Information document for list of genes tested

Guidelines

Allegra C, Jessup M, Somerfield M, Hamilton S, Hammond E, Hayes D, McAllister P, Morton R, Schilsky R. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009; 27(12): 2091-6. PubMed

American Cancer Society Guidelines for the Early Detection of Cancer. American Cancer Society. Atlanta, GA [Accessed: June 2014]

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Duffy M, van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, Lamerz R, Peltomaki P, Sturgeon C, Topolcan O. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer. 2007; 43(9): 1348-60. PubMed

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genet Med. 2009; 11(1): 15-20. PubMed

Hampel H, Bennett R, Buchanan A, Pearlman R, Wiesner G, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1): 70-87. PubMed

Locker G, Hamilton S, Harris J, Jessup J, Kemeny N, Macdonald J, Somerfield M, Hayes D, Bast R, ASCO. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006; 24(33): 5313-27. PubMed

NCCN Clinical Practice Guidelines in Oncology, Colon Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

NCCN Clinical Practice Guidelines in Oncology, Colorectal Cancer Screening. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

NCCN Clinical Practice Guidelines in Oncology, Rectal Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

Protocol for the Examination of Specimens from Patients with Primary Carcinoma of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: October 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Schmoll H, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde C, Balmana J, Regula J, Nagtegaal I, Beets-Tan R, Arnold D, Ciardiello F, Hoff P, Kerr D, Köhne C, Labianca R, Price T, Scheithauer W, Sobrero A, Tabernero J, Aderka D, Barroso S, Bodoky G, Douillard J, Ghazaly E, Gallardo J, Garin A, Glynne-Jones R, Jordan K, Meshcheryakov A, Papamichail D, Pfeiffer P, Souglakos I, Turhal S, Cervantes A. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol. 2012; 23(10): 2479-516. PubMed

Stoffel E, Mangu P, Gruber S, Hamilton S, Kalady M, Lau M, Lu K, Roach N, Limburg P, American Society of Clinical Oncology, European Society of Clinical Oncology. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015; 33(2): 209-17. PubMed

Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3: iii1-9. PubMed

General References

Bedeir A, Krasinskas A. Molecular diagnostics of colorectal cancer. Arch Pathol Lab Med. 2011; 135(5): 578-87. PubMed

Chua W, Moore M, Charles K, Clarke S. Predictive biomarkers of clinical response to targeted antibodies in colorectal cancer. Curr Opin Mol Ther. 2009; 11(6): 611-22. PubMed

Cunningham D, Atkin W, Lenz H, Lynch H, Minsky B, Nordlinger B, Starling N. Colorectal cancer. Lancet. 2010; 375(9719): 1030-47. PubMed

Fearon E. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011; 6: 479-507. PubMed

Newton K, Newman W, Hill J. Review of biomarkers in colorectal cancer. Colorectal Dis. 2012; 14(1): 3-17. PubMed

Ross J. Clinical implementation of KRAS testing in metastatic colorectal carcinoma: the pathologist's perspective. Arch Pathol Lab Med. 2012; 136(10): 1298-307. PubMed

Sharma S, Gulley M. BRAF mutation testing in colorectal cancer. Arch Pathol Lab Med. 2010; 134(8): 1225-8. PubMed

Wilkins T, Reynolds P. Colorectal cancer: a summary of the evidence for screening and prevention. Am Fam Physician. 2008; 78(12): 1385-92. PubMed

Yurgelun M, Goel A, Hornick J, Sen A, Turgeon D, Ruffin M, Marcon N, Baron J, Bresalier R, Syngal S, Brenner D, Boland R, Stoffel E. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res (Phila). 2012; 5(4): 574-82. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Affolter K, Samowitz W, Tripp S, Bronner M. BRAF V600E mutation detection by immunohistochemistry in colorectal carcinoma. Genes Chromosomes Cancer. 2013; 52(8): 748-52. PubMed

Burt R, Leppert M, Slattery M, Samowitz W, Spirio L, Kerber R, Kuwada S, Neklason D, Disario J, Lyon E, Hughes P, Chey W, White R. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology. 2004; 127(2): 444-51. PubMed

Campbell P, Curtin K, Ulrich C, Samowitz W, Bigler J, Velicer C, Caan B, Potter J, Slattery M. Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors. Gut. 2009; 58(5): 661-7. PubMed

Curtin K, Samowitz W, Wolff R, Caan B, Ulrich C, Potter J, Slattery M. MSH6 G39E polymorphism and CpG island methylator phenotype in colon cancer. Mol Carcinog. 2009; 48(11): 989-94. PubMed

Curtin K, Samowitz W, Wolff R, Ulrich C, Caan B, Potter J, Slattery M. Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer. Cancer Epidemiol Biomarkers Prev. 2009; 18(12): 3384-8. PubMed

Curtin K, Slattery M, Ulrich C, Bigler J, Levin T, Wolff R, Albertsen H, Potter J, Samowitz W. Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. Carcinogenesis. 2007; 28(8): 1672-9. PubMed

Curtin K, Ulrich C, Samowitz W, Bigler J, Caan B, Potter J, Slattery M. Thymidylate synthase polymorphisms and colon cancer: associations with tumor stage, tumor characteristics and survival. Int J Cancer. 2007; 120(10): 2226-32. PubMed

Eliason K, Hendrickson B, Judkins T, Norton M, Leclair B, Lyon E, Ward B, Noll W, Scholl T. The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet. 2005; 42(1): 95-6. PubMed

Ferrández A, Pho L, Solomon C, Samowitz W, Kuwada S, Knecht T, Gilfeather M, Burt R. An evidence-based, multidisciplinary approach to the clinical considerations, management, and surveillance of adrenal lesions in familial adenomatous polyposis: report of three cases. Dis Colon Rectum. 2006; 49(11): 1781-90. PubMed

Neklason D, Thorpe B, Ferrández A, Tumbapura A, Boucher K, Garibotti G, Kerber R, Solomon C, Samowitz W, Fang J, Mineau G, Leppert M, Burt R, Kuwada S. Colonic adenoma risk in familial colorectal cancer--a study of six extended kindreds. Am J Gastroenterol. 2008; 103(10): 2577-84. PubMed

Patil D, Bronner M, Portier B, Fraser C, Plesec T, Liu X. A five-marker panel in a multiplex PCR accurately detects microsatellite instability-high colorectal tumors without control DNA. Diagn Mol Pathol. 2012; 21(3): 127-33. PubMed

Rowe L, Bentz B, Bentz J. Detection of BRAF V600E activating mutation in papillary thyroid carcinoma using PCR with allele-specific fluorescent probe melting curve analysis. J Clin Pathol. 2007; 60(11): 1211-5. PubMed

Salk J, Bansal A, Lai L, Crispin D, Ussakli C, Horwitz M, Bronner M, Brentnall T, Loeb L, Rabinovitch P, Risques R. Clonal expansions and short telomeres are associated with neoplasia in early-onset, but not late-onset, ulcerative colitis. Inflamm Bowel Dis. 2013; 19(12): 2593-602. PubMed

Samowitz W, Albertsen H, Sweeney C, Herrick J, Caan B, Anderson K, Wolff R, Slattery M. Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst. 2006; 98(23): 1731-8. PubMed

Samowitz W, Broaddus R, Iacopetta B, Goldblatt J. PCR versus immunohistochemistry for microsatellite instability. J Mol Diagn. 2008; 10(2): 181-2; author reply 181. PubMed

Samowitz W, Curtin K, Wolff R, Albertsen H, Sweeney C, Caan B, Ulrich C, Potter J, Slattery M. The MLH1 -93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer. Genes Chromosomes Cancer. 2008; 47(10): 835-44. PubMed

Samowitz W, Curtin K, Wolff R, Tripp S, Caan B, Slattery M. Microsatellite instability and survival in rectal cancer. Cancer Causes Control. 2009; 20(9): 1763-8. PubMed

Samowitz W, Ogino S. DNA methylation in breast and colorectal cancers. Mod Pathol. 2008; 21(8): 1054; author reply 1054-5. PubMed

Samowitz W, Slattery M, Sweeney C, Herrick J, Wolff R, Albertsen H. APC mutations and other genetic and epigenetic changes in colon cancer. Mol Cancer Res. 2007; 5(2): 165-70. PubMed

Samowitz W, Wolff R, Curtin K, Sweeney C, Ma K, Andersen K, Levin T, Slattery M. Interactions between CYP2C9 and UGT1A6 polymorphisms and nonsteroidal anti-inflammatory drugs in colorectal cancer prevention. Clin Gastroenterol Hepatol. 2006; 4(7): 894-901. PubMed

Samowitz W, Wolff R, Ma K, Andersen K, Caan B, Slattery M. Polymorphisms in insulin-related genes predispose to specific KRAS2 and TP53 mutations in colon cancer. Mutat Res. 2006; 595(1-2): 117-24. PubMed

Samowitz W. Genetic and epigenetic changes in colon cancer. Exp Mol Pathol. 2008; 85(1): 64-7. PubMed

Samowitz W. The CpG island methylator phenotype in colorectal cancer. J Mol Diagn. 2007; 9(3): 281-3. PubMed

Slattery M, Curtin K, Sweeney C, Levin T, Potter J, Wolff R, Albertsen H, Samowitz W. Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer. 2007; 120(3): 656-63. PubMed

Slattery M, Curtin K, Wolff R, Boucher K, Sweeney C, Edwards S, Caan B, Samowitz W. A comparison of colon and rectal somatic DNA alterations. Dis Colon Rectum. 2009; 52(7): 1304-11. PubMed

Slattery M, Curtin K, Wolff R, Ma K, Sweeney C, Murtaugh M, Potter J, Levin T, Samowitz W. PPARgamma and colon and rectal cancer: associations with specific tumor mutations, aspirin, ibuprofen and insulin-related genes (United States). Cancer Causes Control. 2006; 17(3): 239-49. PubMed

Slattery M, Wolff R, Curtin K, Fitzpatrick F, Herrick J, Potter J, Caan B, Samowitz W. Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res. 2009; 660(1-2): 12-21. PubMed

Sweeney C, Boucher K, Samowitz W, Wolff R, Albertsen H, Curtin K, Caan B, Slattery M. Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors. Genes Chromosomes Cancer. 2009; 48(1): 1-9. PubMed

Szankasi P, Reading S, Vaughn C, Prchal J, Bahler D, Kelley T. A quantitative allele-specific PCR test for the BRAF V600E mutation using a single heterozygous control plasmid for quantitation: a model for qPCR testing without standard curves. J Mol Diagn. 2013; 15(2): 248-54. PubMed

Tomsic J, Senter L, Liyanarachchi S, Clendenning M, Vaughn C, Jenkins M, Hopper J, Young J, Samowitz W, de la Chapelle A. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013; 83(3): 238-43. PubMed

Vaughn C, Baker C, Samowitz W, Swensen J. The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. Genes Chromosomes Cancer. 2013; 52(1): 107-12. PubMed

Vaughn C, Lyon E, Samowitz W. Confirmation of single exon deletions in MLH1 and MSH2 using quantitative polymerase chain reaction. J Mol Diagn. 2008; 10(4): 355-60. PubMed

Walter A, Ennis S, Best H, Vaughn C, Swensen J, Openshaw A, Gripp K. Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies. Pediatr Blood Cancer. 2013; 60(11): E135-6. PubMed

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Last Update: January 2016