The Bethesda Guidelines for Testing
Historically, a diagnosis relied on clinical features and family history. The Bethesda Guidelines (2002) were created for the specific purpose of identifying patients who would be a candidate for testing for Lynch syndrome:
- Colorectal cancer diagnosed in a patient < age 50 years.
- Presence of synchronous or metachronous Lynch syndrome–associated tumors, regardless of age.
- Colorectal cancer with MSI-H histology diagnosed in a patient < age 60 years.
- Colorectal cancer diagnosed in a patient with one or more first-degree relatives with a Lynch syndrome–related cancer, with one of the cancers being diagnosed at < age 50 years.
- Colorectal cancer diagnosed in a patient with two or more first or second-degree relatives with Lynch syndrome–related cancers regardless of age.
These augmented testing options are intended to assist clinicians in their diagnosis, management, and treatment of patients affected with Lynch syndrome. In 2009, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group recommended universal genetic testing for individuals with a diagnosis of colorectal cancer.
Types of Lynch Syndrome Tests
One such test is microsatellite instability (MSI) testing. MSI testing identifies tumors caused by defective mismatch repair by comparing nucleotide repeats in a panel of specific markers. Tumor tissue MSI is compared with normal tissue from the same patient. MSI high results may warrant further germline testing. MSI testing has a higher sensitivity for detecting tumors with mutations in the MLH1 and MSH2 genes when compared to screening for mutations in the MSH6 or PMS2 genes. Fortunately, mutations in the MLH1 and MSH2 genes are more common in patients with Lynch syndrome than mutations in MSH6 or PMS2.
Another test that may be used is immunohistochemistry (IHC), which is a protein-staining technique that can identify tumors caused by protein truncation or non-expression. IHC may not detect tumors caused by missense mutations. Utilizing MSI and IHC testing technologies (sequentially or simultaneously) provides the highest sensitivity and specificity given that each test may detect a positive result that screened negative in the other test.
Tumor testing may be followed up with germline testing to identify a familial mutation that diagnoses a patient with Lynch syndrome. This diagnosis allows for other family members to be tested to determine their risk of Lynch syndrome-related cancer as well, regardless of whether that family member is currently diagnosed with cancer.
Universal testing negates the need for complex algorithms to determine who may be a candidate for testing. Additionally, it has shown to be cost-effective and provide information that may assist in determining treatment options. Studies have shown that a diagnosis of Lynch syndrome may impact surgical options for the patient as well. Additionally, it has been demonstrated that patients with stage 2 and 3 colorectal cancer that is MSI-high may not benefit from adjuvant chemotherapy utilizing 5- fluorouracil.
Unfortunately, the literature also reports that tumor testing is inconsistent among clinicians and may even be underutilized. One study surveyed surgeons, oncologists, genetic counselors, and primary care providers, among other stakeholders, to determine their utilization of tumor testing. Testing was offered and performed subjectively without standardization. Although testing may have been indicated for a patient, it was commonly ordered for different reasons, depending on the ordering provider (oncologist, genetic counselor, or pathologist). Surveyed providers expressed support for universal tumor screening for Lynch syndrome. However, some providers reported they were overwhelmed with new (genetic) tests and cannot keep up with the ever-evolving technology. A standard universal testing protocol, as recommended by EGAPP, would mitigate the confusion among providers, increase diagnoses, and may increase cost-effectiveness.
The benefits of universal tumor testing in patients diagnosed with colon cancer may include: increased cost-effectiveness, diagnoses, personalized treatment for the patient, and the ability to identify at-risk (possibly asymptomatic) family members. A standardized universal testing protocol is the least burdensome option for healthcare providers, regardless of their specialties. This method of patient care is also recommended by the National Comprehensive Cancer Network (NCCN), a leading professional organization that specializes in cancer testing, prevention, diagnosis, and treatment. It is very important that providers caring for this patient population implement standardized universal testing for optimal patient care.
- Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part II. The utility of microsatellite instability testing. J Mol Diagn. 2008 Jul;10(4):301-7
- Bombard Y, Rozmovits L, Sorvari A, Daly C, Carroll JC, Kennedy E, Rabeneck L, Baxter NN. Universal tumor screening for Lynch syndrome: health-care providers’ perspectives. Genet Med. 2017 May;19(5):568-574
- Strafford JC. Genetic testing for lynch syndrome, an inherited cancer of the bowel, endometrium, and ovary. Rev Obstet Gynecol. 2012;5(1):42-9
- Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009 Jan;11(1):35-41.
- Leicher LW, Lammertink MHA, Offerman SR, Morreau H, de Jong MM, de Groot JWB, van Westreenen HL, Vasen HFA, de Vos Tot Nederveen Cappel WH. Consequences of testing for mismatch repair deficiency of colorectal cancer in clinical practice. Scand J Gastroenterol. 2018 May;53(5):632-636.