The era of personalized health care has arrived. While everyone is focusing on low penetrance single nucleotide polymorphisms that impart relative risks (RRs) for cancer ranging from 1.2 to 2.0, gene mutations that cause high cancer risks (RRs > 5) are being overlooked. Diagnosing an autosomal dominant, highly penetrant cancer–susceptibility syndrome in patients with cancer may provide important information about their prognosis, treatment, and future cancer risks. In addition, this allows their relatives to undergo genetic counseling and testing to learn if they too are at increased risk for cancer and could benefit from intensive cancer surveillance. The costs of screening can be offset by the benefits of cancer prevention in the patient and their relatives. The best example of this is the current movement to screen all patients with newly diagnosed colorectal cancer for Lynch syndrome using microsatellite instability (MSI) testing or immunohistochemistry (IHC) staining for the mismatch repair (MMR) proteins.
Lynch syndrome is the most common cause of inherited colorectal cancer. With an incidence of 2.8% among all patients with newly diagnosed colorectal cancer,1,2 this syndrome will account for 4200 of the 150,000 colorectal cancers diagnosed in 2010. Individuals with Lynch syndrome have significantly increased risks for colorectal, endometrial, gastric, ovarian, urothelial, sebaceous, and biliary cancers. Although the cancer risks are high, intensive cancer surveillance, including the use of frequent colonoscopy, can significantly reduce cancer-related deaths in individuals with Lynch syndrome.3 Although data are limited regarding the efficacy of transvaginal ultrasound and endometrial biopsies for endometrial cancer surveillance,4–6 hysterectomy and bilateral salpingo-oophorectomy seem to be effective at preventing endometrial and ovarian cancers in women with Lynch syndrome.7
Lynch syndrome is caused by germline mutations in an MMR gene, such as MLH1, MSH2, MSH6, or PMS2. Tumors from individuals with Lynch syndrome usually exhibit MSI, which is an expansion or contraction of areas of DNA composed of nucleotide repeats. In addition, following Knudson's 2-hit hypothesis, Lynch syndrome tumors usually exhibit the absence of at least 1 MMR protein, whereas all proteins are present in normal tissue from individuals with Lynch syndrome. This can be identified using IHC staining of the tumors with antibodies to the 4 MMR proteins. Approximately 12% to 20% of all colorectal cancers exhibit MSI and abnormal IHC.1,2,8–10 These 2 screening tests can be used interchangeably because results show a greater than 94% concordance (tumors with abnormal IHC are MSI-high and vice versa).11
Approximately 75% of colorectal cancer patients whose tumors exhibit MSI or abnormal IHC do not have Lynch syndrome, but instead have acquired hypermethylation of the MLH1 promoter.12,13 Relatives of these patients are not at risk for inheriting Lynch syndrome; however, these patients are subject to the same prognostic and treatment implications that apply to all patients with MSI-high colorectal cancers.
Several methods can help distinguish patients with acquired MLH1 promoter methylation from select patients who would benefit from germline MLH1 gene testing. Without introducing another molecular test, one could avoid germline MLH1 gene testing in patients diagnosed with colorectal cancer older than 60 years of age with no family history of colorectal or endometrial cancer, because these patients are highly likely to have acquired MLH1 promoter methylation.
MLH1 promoter methylation testing can also be assessed directly in tumor DNA; however, concerns exist that this could occasionally be the “second hit” in a patient with a germline MLH1 mutation, and therefore a positive methylation test does not rule out a germline MLH1 mutation completely.
Finally, tumor DNA can be tested for the somatic BRAF mutation V600E. This mutation is found in the tumors of 69% of patients with acquired MLH1 promoter methylation and has not yet been reported in a patient with a germline MLH1 mutation.14 Because this testing is easier and less expensive than methylation testing, it has been implemented routinely as a reflex text in many hospitals that are screening all newly diagnosed colorectal cancer patients for Lynch syndrome when IHC results indicate absence of MLH1 and PMS2. It significantly reduces the number of patients needing further germline testing.
All patients with colorectal cancer should be screened with MSI or IHC because it affects prognosis and the treatment of stage II and III disease and, if they have Lynch syndrome, it will affect their and their relatives' future cancer risks and surveillance.
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