COLARIS®

by Myriad Genetics, Inc.

Lynch Syndrome (HNPCC), MAP

Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is the most common cause of hereditary colon cancer and is believed to account for 3% to 5% of all colorectal cancers.

It is now known that Lynch syndrome results from an inherited mutation in one of the mismatch repair (MMR) genes. Normally, MMR genes produce proteins that identify and correct base-pairing mismatches that can occur during DNA replication. Consequently, a mutation that inactivates an MMR gene leads to accumulation of other mutations which significantly increases the likelihood of developing cancer. Mutations that disrupt the function of MMR genes (mutations in MLH1, MSH2, MSH6, EPCAM, and PMS2) have been linked to Lynch syndrome.

It has been known that germline mutations in MLH1, MSH2 and MSH6 account for the majority of detected mutations in families with Lynch syndrome. More recently it has been discovered that PMS2 and EPCAM also play an important role in Lynch syndrome.

As one of the four primary mismatch repair genes associated with Lynch syndrome, the functional importance of PMS2 has been clear, but its total contribution to Lynch syndrome was historically considered to be quite low. More recent studies suggest that the prevalence of PMS2 mutations is comparable to MSH6, with as much as 15% of all Lynch syndromes attributable to PMS2.

The EPCAM gene is a recently discovered contributor to Lynch syndrome, accounting for an estimated 1-3% of all detectable Lynch syndrome mutations. Studies indicate that large deletions in the end of this gene, which is located directly “upstream” of MSH2, can lead to a loss of MSH2 expression and result in Lynch syndrome.

MYH-associated polyposis (MAP) is caused by mutations in the mutY homolog (MYH) gene. MAP is inherited in an autosomal recessive manner. Individuals with MAP have mutations in both of their MYH genes (one from each parent, often referred to as “biallelic MYH mutations”). Patients often have no family history of colon cancer or polyps in parents (although siblings may be affected). The MYH gene is an important part of the base excision repair (BER) pathway, which allows for repair of DNA mutations caused by oxidative damage to cells. MAP is believed to account for approximately 1% of all colorectal cancers. MAP can cause patients to develop colorectal cancer even in the absence of colon polyposis.

Identifying Patients at Risk for Lynch Syndrome and MAP

Finding patients at risk for Lynch syndrome and following up with them is perhaps the most critical step in potentially changing hereditary cancer outcomes. Although the MYH gene does not cause Lynch syndrome, patients with MYH-associated polyposis (MAP) can develop colorectal cancer even if they do not have a history of colon polyps. The following “red flags” in a patient’s personal or family history may indicate an increased risk for Lynch syndrome and help identify candidates for testing.

An individual with any of the following PERSONAL histories:

  • Colorectal or endometrial cancer before age 50
  • MSI High histology before age 60:
    • Mucinous
    • Signet ring
    • Tumor infiltrating lymphocytes
    • Crohn’s-like lymphocytic reaction histology
    • Medullary growth pattern
  • Abnormal MSI/IHC tumor test result (Colorectal/Endometrial)
  • 2 or more Lynch syndrome cancers at any age
  • Lynch syndrome cancer with 1 or more relatives with a Lynch syndrome cancer
  • A previously identified Lynch syndrome or MAP syndrome mutation in the family

An individual with any of the following FAMILY histories:

  • A first or second degree relative with colorectal or endometrial cancer before age 50
  • Two or more relatives with a Lynch syndrome cancer, one before age 50
  • Three or more relatives with a Lynch syndrome cancer at any age
  • A previously identified Lynch syndrome or MAP syndrome mutation in the family

COLARIS® Testing

COLARIS® is a genetic test that assesses a person’s risk of developing hereditary colorectal cancer and a woman’s risk of developing hereditary uterine (endometrial) cancer. COLARIS® detects disease-causing mutations in the MLH1, MSH2, MSH6, PMS2 and MYH genes that are responsible for the majority of Lynch syndrome and MYH-associated polyposis (MAP) cases.

Benefits of COLARIS® Testing

The results of the COLARIS® test enable the development of a patient-specific medical management roadmap to significantly reduce the risk of cancer. COLARIS® will help you to:

  • Target increased surveillance and other interventions specifically to individuals with a Lynch syndrome or MYH-associated polyposis mutation(s)—maximizing patient care and increasing clinical efficiency
  • Improve patient compliance with tailored screening recommendations and preventive measures
  • Significantly improve outcomes and reduce medical costs through prevention, earlier diagnosis and treatment of cancer, should it develop
  • Counsel patients and family members on the underlying cause of cancer in their family
  • Avoid unnecessary interventions for family members who do not test positive for the mutation(s) known to be in the family

Managing Patients with Lynch Syndrome or MYH-associated Polyposis (MAP)

Once a diagnosis of Lynch syndrome is confirmed, the following medical management options may help reduce cancer risk or detect cancer at an earlier, more treatable stage or even prevent it.

Lynch Syndrome Management:

Colon Cancer

Increased Surveillance for Colorectal Cancer

  • Colonoscopy ever 1-2 years beginning between age 20 and 25, OR 10 years before the earliest age of a patient’s family member diagnosed with colorectal cancer – whichever comes first.
  • Consider annual colonoscopy after age 40.
  • For MSH6 mutation carriers consider initiating colonscopy screening at age 30 – 35 or 10 years before the earliest age of a patient’s family member diagnosed with colorectal cancer. This is due to the later average age of onset in MSH6 mutation carriers.

Surgical Management of Colorectal Cancer

  • If colon cancer is diagnosed (or more than one advanced adenoma is found) in a patient with Lynch syndrome, total colectomy with ileorectal anastomosis OR hemicolectomy is an option.
  • In patients unwilling or unable to undergo periodic colonscopy screening, prophylactic total colectomy with ileorectal anastomosis may be an option based on carrier status alone.

Endometrial and Ovarian Cancer

Surveillance for Endometrial and Ovarian Cancer

  • Consideration of referral to a gynecologic oncologist to discuss screening options with can include gynecologic exam, transvaginal ultrasound, endometrial aspiration and CA-125 every year, beginning between age 25 and 35.

Surgical Management of Endometrial and Ovarian Cancer

  • Prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy is a risk reducing option for women who have completed childbearing
  • May also be considered at time of colon surgery if postmenopausal or childbearing is complete.

Surveillance for Other Lynch Syndrome-Related Cancers

  • For gastric and duodenal cancer: Consider upper GI endoscopy (wide side viewing scope) at age 25 – 30 years and repeat every 1 to 3 years depending on findings
  • For urothelial cancer: Consider urinalysis on an annual basis
  • For CNS cancer: Physical examination on an annual basis

MYH-Associated Polyposis (MAP) Management:

  • For patients who have MAP, medical society management recommendations include colonoscopies every 1-2 years starting at age 25-30, upper endoscopies every 3-5 years starting at age 30-35, and surgical considerations. The most appropriate medical management will vary based upon your patient’s clinical presentation.
  • For MYH mutation carriers (1 mutation), medical management should be determined by clinical findings and personal and family history of colorectal polyps and/or cancer. Current data are limited but suggest that any increase in risk, if present, is likely to be small.

What is the unique advantage of Myriad COLARIS® testing?

Over the last 20 years, Myriad has delivered more than one million test results. Results are reviewed rigorously in a strict quality control process, with a second round of testing for reportable mutations.  Myriad has the lowest VUS rate globally with a less than 8% VUS rate for the gene mutations associated with Lynch Syndrome. A lower VUS rate means a lower chance of resulting in an uncertain result, which means more confidence and clarity in your results.

COLARIS® FAQs

[accordion][accordion-item title="How do I order a test?"]Please contact us and let us know if you would like to order a test for a patient. One of our representatives will get in touch with you and advise on the workflow, and provide the necessary forms and sample collection kits. Once the samples have been collected, we will coordinate the shipment of the sample to the laboratory. Once testing is completed, the report will be sent to you.[/accordion-item][accordion-item title="How is the COLARIS® test performed?"]A small amount of blood is drawn and the sample is sent to Myriad Genetic Laboratories, Inc for DNA sequencing analysis of MLH1, MSH2, MSH6, PMS2 and MYH. COLARIS can also detect large rearrangements in MLH1, MSH2, MSH6, EPCAM, PMS2 and MYH that will not be identified by gene sequencing.[/accordion-item][accordion-item title="How long does it take for COLARIS® test results?"]Results take about 3-4 weeks from the time the sample reaches the lab.[/accordion-item][accordion-item title="If a patient has already been diagnosed with cancer, what does a positive COLARIS® result indicate?"]Individuals with Lynch syndrome gene mutations are at greater risk for developing a new cancer, in either the colon, endometrium or other areas. Knowing a patient’s genetic status can help reduce this risk or detect another potential cancer at an early, more treatable stage. Importantly, a patient’s test results also have significant meaning for the health of his or her family members.[/accordion-item][/accordion]