Lynch syndrome is a hereditary cancer syndrome that places individuals at an increased risk for colorectal, endometrial, stomach, ovarian, urothelial, and other cancers.1 It is caused by mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. In addition, a deletion in the EPCAM gene results in Lynch syndrome by inactivating the MSH2 gene. Thus, mutations in ≥5 genes can result in Lynch syndrome. Historically, a diagnosis relied on clinical and family history features to prompt germline testing; however, because Lynch syndrome can have diverse presentations, sensitivity and specificity of this approach was low.
A method that has been shown to increase the diagnosis of Lynch syndrome is tumor-based screening. Tumor-based screening is typically performed on colorectal or endometrial tumors, and looks for features of MMR deficiency. This is typically done using polymerase chain reaction–based microsatellite instability (MSI) testing to look for differences in genomic repeats and/or immunohistochemistry (IHC) analysis for expression of the MMR proteins.1
It is believed that MSI and/or IHC testing can identify up to 95% of Lynch syndrome–associated colorectal cancers.2 Therefore, screening colorectal cancer samples for MMR deficiency can be used to help identify patients at risk for Lynch syndrome. As a result, many institutions test every newly diagnosed colorectal cancer specimen—referred to as universal screening—for MMR deficiency, and the practice is supported by multiple professional organizations.2,3 However, patients with Lynch syndrome are not the only individuals who develop MMR-deficient colorectal cancer tumors.
Of the 15% of colorectal cancer cases with MMR deficiency, approximately 80% will not have a germline mutation associated with Lynch syndrome.2-5 In these cases, the cause of the MMR-deficient colorectal cancer tumor is typically somatic and caused by hypermethylation of the MLH1 promoter and epigenetic silencing of MLH1 or double somatic mutations in the MMR genes.2-5 Determining whether a patient’s MMR-deficient colorectal cancer tumor is caused by somatic or germline findings is crucial for determining a patient’s treatment plan, future cancer risks, and cancer risks of relatives.
The typical process for determining the cause of a patient’s MMR-deficient colorectal cancer tumor depends on whether MSI or IHC were performed. For patients who exhibit MSI-high tumors or loss of expression of both MLH1 and PMS2, the next step is typically ordering BRAF V600E somatic testing or MLH1 promoter methylation analysis. If either the BRAF V600E mutation or MLH1 promoter methylation are present, testing usually stops, and it is assumed the patient does not have Lynch syndrome. If neither of these are found or the patient has a different loss of expression pattern for the MMR genes on IHC, germline testing for Lynch syndrome is usually the next step.
If a germline mutation for Lynch syndrome is found, genetic testing typically stops and the patient is diagnosed with Lynch syndrome. However, if a patient is not found to have a mutation associated with Lynch syndrome, the BRAF V600E somatic mutation, or MLH1 promoter methylation, the patient’s phenotype is sometimes referred to as “Lynch-like,” and clinical judgment comes into play regarding whether these cases should be managed as Lynch syndrome without an identifiable germline mutation, or more like a sporadic colorectal cancer case.2,4 These cases create great frustration for clinicians and for patients, as their Lynch syndrome status is unclear.
Thankfully, in the past decade, there have been improvements in the analyzation of large amounts of genetic data, as well as a decrease in the cost to do so. This has provided the ability to analyze and compare somatic and germline tumor mutations. Because all cancer is genetic, it makes sense that tumors can contain variants that are unique and only found in the tumor, but tumors may also contain variants that are found in the germline. This is also the case with Lynch syndrome and MMR-deficient colorectal cancer tumors. By chance, a person can have 2 MMR mutations that are only found in their colorectal cancer tumor and not found in their germline.6 Therefore, a person’s colorectal cancer tumor would have MMR deficiency, but he or she would not have Lynch syndrome. This molecular class of MMR-deficient colorectal cancer tumors has recently been dubbed double somatic MMR-mutated colorectal cancer.
Double somatic MMR mutations account for up to 70% of colorectal cancer cases where MMR deficiency is not explained by MLH1 hypermethylation or a germline mutation for Lynch syndrome.7,8 If double somatic MMR mutations are found, they are deemed to be the cause of the patient’s MMR-deficient colorectal cancer tumor, and the patient is managed based on personal and family history, not on the basis of having Lynch syndrome. During the past several years, somatic MMR genetic testing has been incorporated into Lynch syndrome testing strategies for abnormal tumor results, and genetic testing companies have developed tests that analyze germline and somatic MMR mutations at the same time.2 As concurrent somatic and germline MMR genetic testing is relatively new, patients who were previously found to have unexplained MMR-deficient colorectal cancer tumors may benefit from updated testing consisting of somatic MMR genetic testing and/or a multigene inherited cancer panel.
In addition to increasing the diagnostic yield of Lynch syndrome, it is important to screen colorectal cancer tumors for MMR deficiency for therapeutic reasons. During early disease stages, these tumors are known to have a better prognosis than those without MMR deficiency, but they also tend to benefit less from 5-fluorouracil chemotherapy.5 Patients with MMR-deficient tumors may also be candidates for PD-L1/PD-1 immunotherapy.9 In addition, it is known that other somatic mutations outside of the MMR spectrum, such as KRAS and NRAS, have therapeutic implications.10
Somatic analysis of colorectal cancer specimens can help guide therapeutic decisions, as well as genetic testing strategies. There is also no question that universal tumor screening has helped identify individuals with Lynch syndrome. However, universal screening was first implemented before next-generation sequencing and multigene panels were commonplace. As more is learned about tumorigenesis and Lynch syndrome, the algorithm for diagnosing Lynch syndrome becomes more complex, and often requires multiple steps, which can be time-intensive and create patient anxiety. Because of the importance of somatic findings in colorectal cancer management, as well as their ability to help resolve up to 68% of discordant tumor screening and germline Lynch syndrome test results,2 is it time to consider creating a universal colorectal cancer tumor screen with somatic testing as a first step?
1. Kohlmann W, Gruber SB. Lynch syndrome. Updated May 22, 2014. www.ncbi.nlm.nih.gov/books/NBK1211/. Accessed July 15, 2017.
2. National Comprehensive Cancer Network. NCCN Guidelines for Genetics/Familial High-Risk Assessment (NCCN Guidelines): Colorectal Cancer. Version 1.2017. December 6, 2016. www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed July 15, 2017.
3. Lynch Syndrome Screening Network. www.lynchscreening.net. Accessed July 15, 2017.
4. Carethers JM. Differentiating Lynch-like from Lynch syndrome. Gastroenterology. 2014;146:602-604.
5. Haraldsdottir S, Hampel H, Wu C, et al. Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognosis. Genet Med. 2016;18:863-868.
6. Ngeow J, Eng C. Precision medicine in heritable cancer: when somatic tumour testing and germline mutations meet. Published January 13, 2016. www.nature.com/articles/npjgenmed20156. Accessed July 15, 2017.
7. Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology. 2013;144:926-932.
8. Haraldsdottir S, Hampel H, Tomsic J, et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014;147:1308-1316.
9. Le D, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med. 2015;372:2509-2520.
10. Morkel M, Riemer P, Bläker H, Sers C. Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance. Oncotarget. 2015;6:20785-20800.