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ColoTrue®

Genetic Test for Colorectal Cancer

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COLORECTAL CANCER

According to the Centers for Disease Control and Prevention (CDC) and the American Cancer Society, colorectal cancer is the second leading cause of cancer-related death in the United States, and the third most commonly diagnosed cancer in men and women. Overall, 1 in 20 individuals will develop colorectal cancer at some point during their life – equating to an approximately 5% lifetime risk of developing colorectal cancer. Although the majority of colorectal cancer is sporadic, and caused by a variety of genetic and non-genetic factors, research has shown that approximately 5% of colorectal cancers are due to hereditary changes in single genes.

WHAT IS COLOTRUE®?

ColoTrue® is a 14-gene hereditary cancer panel for individuals and families with features suggestive of hereditary colorectal cancer. This panel includes full sequencing and deletion/duplication analysis of 13 genes as well as deletion/duplication analysis of the EPCAM gene. In addition, this test also offers site-specific analysis of the MDM2–SNP309 allele. A pathogenic variant in any of these genes warrants consideration of increased colorectal cancer surveillance.

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CLINICAL IMPLEMENTATION FOR PATIENTS

ColoTrue® test can help physicians assess patient’s risk of hereditary colorectal cancer and guide the level and frequency of cancer surveillance. If the results are positive, other at-risk family members may also benefit from ColoTrue® testing.

LEARN MORE ABOUT COLOTRUE®

Many of the genes tested in ColoTrue® are also associated with other cancers and hereditary syndromes.

TEST SPECIFICATIONS

ColoTrue® analyzes the coding and flanking regions (+/- 20 bp) of 13 genes associated with hereditary colorectal cancer (APC, BMPR1A, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53) by next-generation sequencing-based (NGS) and Sanger confirmation of reported gene variants. Additionally, site-specific analysis is performed to test for the variant defined as SNP309T>G in the MDM2 gene. Sanger fill-in is used for all genes in areas of low coverage, which is defined as a read depth of less than 25x. Gross deletions and duplications in the aforementioned 13 genes and EPCAM are identified by microarray analysis and multiplex ligation-dependent probe amplification (MLPA). Suspected deletions in exons 13-15 of PMS2 are confirmed with long range PCR to exclude the pseudogene signal.

TESTING OPTIONS

Below are the next-generation sequencing tests that Pathway Genomics offers for risk of hereditary colorectal cancer:
  1. LynchSyndromeTrue®
  2. ColoTrue®
  3. Single Site Testing

Reflex Options

  1. LynchSyndromeTrue® with reflex to ColoTrue®

ColoTrue®

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LynchSyndromeTrue® with Reflex to ColoTrue®

Step 1:

ColoTrue® must be ordered by a physician, and patients are required to fill out a clinical history questionnaire to determine eligibility.
Physicians can request test kits here.

Step 2:

Patient’s saliva or blood sample is collected in the ColoTrue® test kit and sent back to Pathway Genomics, along with the required paperwork.

Step 3:

Pathway Genomics analyzes your sample in its CLIA-certified and CAP-accredited laboratory. Typically within two to three weeks, your personalized results will be available to the ordering health care professional. The results will then be released to you. Pathway Genomics has a team of genetic counselors who are available to ensure that you understand the information in your report, and to answer any questions you may have about your results . To contact our genetic counselors, please call our client services department at 877-505-7374 or email clientservices@pathway.com.

Individuals who meet one or more of the following criteria should consider genetic testing for colorectal cancer:

  • History of early onset colorectal or endometrial cancer (
  • History of ≥ 10 adenomas or polyps
  • History of two of more associated cancers*
  • Two or more relatives with associated cancers,* with one diagnosed <50yrs
  • Three or more relatives with related cancers* at any age
  • Abnormal MSI and/or IHC testing

*Associated cancers are listed in the table below.

Associated Cancers

Positive for a Pathogenic or Likely Pathogenic Variant Detected

A variant was found that is known to be, or strongly thought to be, associated with an increased risk of developing certain cancer types. This does not mean the individual will develop cancer. Each pathogenic variant may convey a different specific risk of developing cancer in the individual’s lifetime. The report may specify the increased risk for the variant we identified or may give the general risks for the gene in which the variant was found.

Variant of Uncertain Significance Detected

A variant was detected, but at this time it is unclear whether the variant is associated with an increased risk of cancer or instead, is just a benign (non-harmful) change. As new information emerges about the variant, we will update the physician about possible changes to the risk assessment.

 

No Variant Detected

Although no variants known to increase the risk for cancer were found, this does not mean the individual will not develop cancer. The physician will determine the level of screening that is appropriate for the patient.

EXPLORE THE GENES

Pathogenic variants in APC (adenomatous polyposis coli) gene are associated with familial adenomatous polyposis (FAP). The classic form of FAP is characterized by the presence of hundreds to thousands of adenomatous polyps (adenomas) in the colon and rectum, beginning as early as childhood1, 2. In the attenuated form of FAP (AFAP), fewer than one hundred colorectal adenomatous polyps are present and diagnosis of cancer is, on average, 15 years later than in classic FAP cases.

FAP is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline APC pathogenic variant in one of the two copies of the APC gene. FAP patients have a 95% lifetime risk of developing colon cancer and 12% risk of small intestine cancer, compared to 5% and 0.2%, respectively, in the general population1, 3.

The APC gene encodes a protein that negatively regulates the Wnt signaling pathway through inhibiting the beta-catenin protein4. The Wnt signaling pathway controls cell growth and cell differentiation in various organs including the intestine, skin, immune system, bone, and brain5.

Pathogenic variants in BMPR1A (bone morphogenetic protein receptor, type 1A) gene are associated with juvenile polyposis syndrome (JPS). JPS is characterized by benign hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum6, 7.

JPS is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline BMPR1A pathogenic variant in one of the two copies of the BMPR1A gene. JPS patients have a 39% lifetime risk of developing colorectal cancer and 21% risk of gastrointestinal cancer, compared to 5% and 1.5%, respectively, in the general population1, 3, 8, 9.

The BMPR1A gene encodes a serine/threonine kinase that serves as a type I transmembrane receptor for the BMP signaling pathway10, 11. With more than 30 cytokines in the TGF-beta superfamily, the TGF-beta/BMP signaling pathways control numerous biological processes, including growth inhibition, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix remodeling and immune suppression10, 12.

Pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer syndrome (HDGC). Individuals who carry a pathogenic variant in CDH1 have a high risk of developing lobular breast cancer and diffuse gastric cancer at a relatively young age. Onset occurs anywhere between the ages of 14 to 69 years with an average onset age of 38 years [16]. The lifetime risk for female breast cancer in individuals with HDGC is 39-52% and up to 80% for gastric cancer [17, 18].

The CDH1 (cadherin 1) gene encodes the epithelial cadherin protein (E-cadherin), a member of the trans-membrane glycoprotein family. E-cadherin is expressed on epithelial tissues and is responsible for calcium-dependent cell-cell adhesion. Loss of CDH1 expression is associated with cancer cell invasiveness [18]. Individuals who are carriers of a CDH1 germline pathogenic variant, will develop cancer only when the second copy of the CDH1 gene is somatically inactivated or down regulated [17-20].

Pathogenic variants in CHEK2 (checkpoint kinase 2) gene increases the susceptibility of developing certain cancers such as breast cancer20-22, prostate cancer23-25 and colorectal cancer24, 26.
The CHEK2 gene encodes a checkpoint protein kinase important for maintaining genome integrity27. The CHEK2 protein transduces DNA damage response signals detected by the ATM protein kinase28, 29. The ATM-CHEK2 DNA damage response pathway halts cell divisions to provide time for DNA repair, or to initiate programmed cell death (apoptosis) if the damage is irreversible. The CHEK2 protein interacts with other cancer susceptibility gene products such as the p53 and BRCA1 tumor suppressor proteins30, 31.

Pathogenic variants in EPCAM (epithelial cell adhesion molecule) gene are associated with Lynch syndrome. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), accounts for 2-4% of all colorectal cancer cases and with a population incidence of ~1 in 400-5001, 32-37. Lynch syndrome also accounts for 2-5% of all diagnosed endometrial cancer cases34, 38-40, and confers an increased risk of ovarian, gastric, small bowel, hepatobiliary, pancreatic, brain, urothelial and skin cancers32, 36, 41, 42.

Lynch syndrome is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline pathogenic variant in one of the two copies of a Lynch syndrome susceptible gene. Lynch syndrome is typically caused by germline variants in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or in EPCAM1, 35, 43, 44. MMR machinery is responsible for correcting errors during DNA replication.

The EPCAM gene encodes an epithelial cellular adhesion molecule with important role in carcinogenesis45. EPCAM is located upstream of the MSH2 gene. Germline deletions of the 3’ exons or untranslated region (UTR) of EPCAM result in transcriptional read-through of EPCAM and inactivation of the MSH2 gene, leading to increased risk of developing multiple malignancies associated with Lynch syndrome46.

Pathogenic variants in MLH1 (mutL homolog 1) gene are associated with Lynch syndrome. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), accounts for 2-4% of all colorectal cancer cases and with a population incidence of ~1 in 400-5001, 32-37. Lynch syndrome also accounts for 2-5% of all diagnosed endometrial cancer cases34, 38-40, and confers an increased risk of ovarian, gastric, small bowel, hepatobiliary, pancreatic, brain, urothelial and skin cancers32, 36, 41, 42.

Lynch syndrome is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline pathogenic variant in one of the two copies of a Lynch syndrome susceptible gene. Lynch syndrome is typically caused by germline variants in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or in EPCAM1, 35, 43, 44. Individuals who have MLH1 pathogenic variants have a 41% lifetime risk of developing colorectal cancer42. In addition, females carrying MLH1 pathogenic variants have a 54% risk of developing endometrial cancer and a 20% risk of developing ovarian cancer32, 42. Pathogenic variants in MLH1 and MSH2 account for 80-90% of identified variants associated with Lynch syndrome36, 43, 47.

The MMR machinery is responsible for correcting errors during DNA replication. MLH1 dimerizes with PMS2 and forms the MutLα complex with additional MMR proteins48-50. Defects in MMR machinery can lead to microsatellite instability and increased mutability of oncogenes and tumor suppressor genes51.

An MDM2 (Mouse double minute 2) variant (SNP309) has been associated with earlier age of cancer diagnosis in patients with TP53 variants52-59. Variants in the TP53 gene are found in approximately half of all cancers and are usually somatic alterations that are acquired within the cancer itself. Germline, or inheritable, pathogenic variants in TP53 lead to Li-Fraumeni syndrome (LFS)60-62. LFS is characterized by predisposition to multiple early onset cancers and at least 70% of clinically diagnosed LFS cases are associated with germline variants in the TP53 gene61. LFS and its variant, Li-Fraumeni-like (LFL) syndrome are inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline TP53 pathogenic variant in one of the two copies of the TP53 gene.

The MDM2 gene encodes an E3 ubiquitin protein ligase that negatively regulates the p53 tumor suppressor protein, encoded by the TP53 gene63. p53 controls key pathways that protect cells from malignant transformation. MDM2 and p53 interact in a feedback loop, in which p53 facilitates MDM2 transcription and in turn, MDM2 binds, inhibits and degrades p53 through E3 ligase activity63. Over expression of MDM2 leads to down-regulation of p53 pathways and accelerated tumor formation53.

Pathogenic variants in MSH2 (mutS homolog 2) gene are associated with Lynch syndrome. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), accounts for 2-4% of all colorectal cancer cases and with a population incidence of ~1 in 400-5001, 32-37. Lynch syndrome also accounts for 2-5% of all diagnosed endometrial cancer cases34, 38-40, and confers an increased risk of ovarian, gastric, small bowel, hepatobiliary, pancreatic, brain, urothelial and skin cancers32, 36, 41, 42.

Lynch syndrome is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline pathogenic variant in one of the two copies of a Lynch syndrome susceptible gene. Lynch syndrome is typically caused by germline variants in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or in EPCAM1, 35, 43, 44. Individuals who have MSH2 pathogenic variants have a 48% lifetime risk of developing colorectal cancer42. In addition, females carrying MSH2 pathogenic variants have a 21% lifetime risk of developing endometrial cancer and a 24% risk of developing ovarian cancer32, 42. Pathogenic variants in MLH1 and MSH2 account for 80-90% of identified variants associated with Lynch syndrome36, 43, 47.

The MMR machinery is responsible for correcting errors during DNA replication. MSH2 dimerizes with MSH3 or MSH6 and facilitates DNA repair in concert with additional MMR proteins48-50. Defects in MMR machinery can lead to microsatellite instability and increased mutability of oncogenes and tumor suppressor genes51.

Pathogenic variants in MSH6 (mutS homolog 6) gene are associated with Lynch syndrome. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), accounts for 2-4% of all colorectal cancer cases and with a population incidence of ~1 in 400-500 1, 32-37. Lynch syndrome also accounts for 2-5% of all diagnosed endometrial cancer cases34, 38-40, and confers an increased risk of ovarian, gastric, small bowel, hepatobiliary, pancreatic, brain, urothelial and skin cancers32, 36, 41, 42.

Lynch syndrome is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline pathogenic variant in one of the two copies of a Lynch syndrome susceptible gene. Lynch syndrome is typically caused by germline variants in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or in EPCAM1, 35, 43, 44. MSH6 accounts for approximately 10% of the pathogenic variants associated with Lynch syndrome32, 43, 47. Individuals who have MSH6 pathogenic variants have a 12% lifetime risk of developing colorectal cancer, compared to 5% risk in the general population3, 42.

The MMR machinery is responsible for correcting errors during DNA replication. MSH6 dimerizes with MSH2 and facilitates DNA repair in concert with additional MMR proteins48-50. Defects in MMR machinery can lead to microsatellite instability and increased mutability of oncogenes and tumor suppressor genes51.

Pathogenic variants in MUTYH (mutY homolog) gene are associated with MUTYH-associated polyposis (MAP). MAP is characterized by the presence of adenomatous polyposis of the colorectum64, 65.

MAP is inherited in an autosomal recessive pattern, that is, the syndrome can manifest when an individual has a pathogenic variant in both copies of the MUTYH gene, one from each parent. Biallelic germline pathogenic variants in the MUTYH gene increase the risk of developing colorectal cancer and may increase the risk of gastric, endometrial, thyroid and liver cancers64-67. Individuals with a single germline pathogenic variant in MUTYH may also be offered increased surveillance for colorectal cancer, depending on their family history68.

The MUTYH gene encodes a base excision repair glycosylase protein that prevents DNA damage caused by oxidized DNA bases, specifically 8-hydroxyguanine66. Loss of MUTYH activity results in the accumulation of somatic mutations in other genes, including the APC gene, and results in development of adenomas69.

Pathogenic variants in PMS2 (PMS2 postmeiotic segregation increased 2 (S. cerevisiae)) gene are associated with Lynch syndrome. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), accounts for 2-4% of all colorectal cancer cases and with a population incidence of ~1 in 400-5001, 32-37. Lynch syndrome also accounts for 2-5% of all diagnosed endometrial cancer cases34, 38-40, and confers an increased risk of ovarian, gastric, small bowel, hepatobiliary, pancreatic, brain, urothelial and skin cancers32, 36, 41, 42.

Lynch syndrome is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can manifest when an individual has a germline pathogenic variant in one of the two copies of a Lynch syndrome susceptible gene. Lynch syndrome is typically caused by germline variants in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or in EPCAM1, 35, 43, 44. PMS2 accounts for less than 5% of the pathogenic variants associated with Lynch syndrome43. Individuals who have PMS2 pathogenic variants have a 10-15% lifetime risk of developing colorectal cancer, compared to 5% risk in the general population70.

The MMR machinery is responsible for correcting errors during DNA replication. PMS2 dimerizes with MLH1 and forms the MutLα complex with additional MMR proteins48-50. Defects in the MMR machinery can lead to microsatellite instability and accumulation of mutations in the genomic DNA51.

Pathogenic variants in the PTEN gene are associated with PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome (30). Individuals with PHTS develop benign (non-cancerous) tumors called hamartomas in multiple organ systems throughout the body [29, 30]. Individuals with inherited pathogenic variants in the PTEN gene have an elevated risk of breast (85.2% lifetime risk), thyroid (35.2% lifetime risk), endometrial (28.2% lifetime risk) and kidney cancer (33.6% lifetime risk) [31]. These individuals are also prone to developing gastrointestinal polyps and have a slightly elevated lifetime risk for colorectal cancer [30].

The PTEN (phosphatase and tensin homolog) gene encodes a dual-specificity phosphatase that acts on both lipid and protein substrates. The lipid phosphatase activity of the PTEN protein suppresses the PI3K/AKT/mTOR signaling pathway, which regulates cell growth and survival [32]. The importance of PTEN as a tumor suppressor gene is supported by the high frequency of somatic mutations in PTEN found in a variety of sporadic (non-hereditary) human cancers [33].

Pathogenic variants in SMAD4 (SMAD family member 4) gene are associated with juvenile polyposis syndrome (JPS). JPS is characterized by benign hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum6, 7, 76. Patients with SMAD4 pathogenic variants have both JPS syndrome as well as hereditary hemorrhagic telangectasia (HHT) syndrome, which can present with bleeding from vascular malformations that grow over time in the nose, gastrointestinal tract, brain, lungs and liver7, 76.

JPS is inherited in an autosomal dominant pattern, passed from a parent to a child. The syndrome can be manifested by having a germline SMAD4 pathogenic variant in one of the two copies of the SMAD4 gene. JPS patients have a 39% lifetime risk of developing colorectal cancer and 21% risk of gastrointestinal cancer, compared to 5% and 1.5%, respectively, in the general population1, 3, 8, 9.

The SMAD4 gene encodes an intracellular signaling protein that is a common core component of all the TGF-beta/BMP signal transduction pathways that respond to more than 30 cytokines in the TGF-beta superfamily. These signaling pathways control numerous biological processes, including growth inhibition, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix remodeling and immune suppression10, 12.

Pathogenic variants in STK11 are associated with Peutz-Jeghers syndrome (PJS). Individuals with PJS have an increased risk for breast cancer (32-54% lifetime risk), colorectal, gastric, gynecologic, pancreatic and lung cancers, as well as tumors of the testes and gastrointestinal polyps [34-36]. The risks among individuals with PJS for developing any first cancer by ages 20, 30, 40, 50, 60 and 70 years are 2%, 5%, 17%, 31%, 60% and 85%, respectively [37]. In PJS, cancers develop at an average age of 42 years, a younger age compared to the general population [36]. Some individuals with an STK11 pathogenic variant may present with hyperpigmented (dark, freckle-like) spots on mucocutaneous (lips, mouth, nostrils) surfaces that may resolve by adulthood [38].

The STK11 (serine/threonine protein kinase 11) gene encodes a serine-threonine kinase involved in regulation of metabolism, cell differentiation, proliferation, polarity and apoptosis [38, 39]. Most patients who are clinically diagnosed with PJS have a causative mutation in STK11 [40]. Loss of kinase activity is likely responsible for the development of this condition [41].

Pathogenic variants in the TP53 gene are associated with Li-Fraumeni syndrome (LFS). Fifty percent of individuals with a TP53 pathogenic variant will develop cancer by the age of 30 [42-45]. Females who carry a TP53 pathogenic variant have a significant higher risk of developing cancer than male carriers, and a lifetime breast cancer risk of about 70-90% [42, 45-48]. The most common cancers associated with LFS are breast, sarcoma, brain tumors and adrenocortical carcinoma. Other cancers include leukemia, choroid plexus papilloma, Wilms tumor, and gastric, colorectal and pancreatic cancer [49].

The TP53 (tumor protein p53) gene encodes a transcription factor (p53 protein) that is involved in cellular responses to environmental and genotoxic stress [50]. The p53 tumor suppressor protein binds consensus DNA in the responsive elements of several hundreds of genes [51]. Approximately 95% of p53 pathogenic variants are localized in the DNA-binding domain of the p53 protein [51].

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HOW IT WORKS

This simple saliva- or blood-based test is supported by scientifically validated genetic testing technologies, using clinically relevant markers and assays. In just 2-3 weeks, the ColoTrue® report will be delivered to the physicians.

ColoTrue Report Patient 3up

REPORTS: A SIMPLE GUIDE TO UNDERSTANDING

Based on the individual’s unique genetic profile, ColoTrue® provides information that enables the physician to:

✓ Assess patient’s genetic risks of developing colorectal cancer and other hereditary syndromes

✓ Increase cancer surveillance if pathogenic variant(s) are identified

✓ Determine if other family members may benefit from additional testing

GET THE PATHWAY GENOMICS APP TODAY!

  • Access an interactive version of your report anytime, anywhere

  • Learn about other Pathway tests and how they can help you lead a healthier life

  • Help your friends and family by sharing the power of genetic insight

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