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Combined testing protocol may improve Lynch syndrome screening
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Combined tumor microsatellite instability typing, MLH1 methylation and immunohistochemistry analysis may serve as an effective screening process for Lynch syndrome in women with endometrial cancer, according to research published in Journal of Clinical Oncology.
Further, because a large proportion of mutation carriers presented with endometrial cancer before age 60 years, restricting Lynch syndrome testing to women diagnosed at age 60 years or older may miss a substantial portion of genetic disease, according to the researchers.
Between 2% and 6% of women with endometrial cancer are thought to have Lynch syndrome, according to study background. A majority of families with Lynch syndrome have mutations in MSH2, MLH1, MSH6, PMS2 or EPCAM. However, the best screening practice for Lynch syndrome remains unclear.
Thus, Paul J. Goodfellow, PhD, professor of obstetrics and gynecology at The Ohio State University Comprehensive Cancer Center, and colleagues sought to determine whether tumor microsatellite instability (MSI) typing, combined with immunohistochemistry (IHC) and MLH1 methylation, could aid in the identification of women with Lynch syndrome.
Goodfellow and colleagues evaluated tumor samples from 1,002 women with endometrial cancer (mean age, 62.1 years; range, 25-100) enrolled in a Gynecologic Oncology Group clinical trial (GOG-210). Researchers assessed the tumors for MSI, MLH1 methylation and mismatch repair (MMR) protein expression.
Researchers identified 28.4% of tumors as MSI high and 2.8% as MSI low. The mean methylation value of MSI-low tumors was 10.3%, and 18.1% of MSI-high tumors lacked methylation.
The average methylation for 391 microsatellite stable tumors assessed by pyrosequencing was 4.58% (range, 0-92.1), and 21 methylated tumors with a mean methylation of 37.8% expressed MLH1.
Researchers used these data to classify tumors as having normal MMR (no MSI, no IHC defect), defective MMR (MSI positive, methylation, absent MLH1) or probable MMR mutation (absence of MLH1 methylation and MSI and/or MSI and IHC defect).
Overall, 61.6% were MMR normal, 26.5% were MMR defective and 11.9% of tumors (n = 119) had a probable MMR mutation. Women whose tumors were probable for an MMR mutation had the highest family history suggestive of Lynch syndrome (P = .001).
Out of 51 patients classified as having a probable mutation, Lynch mutations were identified in 41% (n = 21). The researchers observed an MSH6 Lynch mutation in a patient whose tumor had intact MSH6 expression.
Mutation carriers had a younger age at diagnosis than noncarriers (54.3 years vs. 62.3 years; P < .01). Five carriers were diagnosed after age 60 years.
“Our analysis of a large cohort of endometrioid endometrial cancer points to the importance of combined IHC, methylation and MSI tumor typing in Lynch screening and the need to evaluate women diagnosed at younger than 60 years,” Goodfellow and colleagues wrote. “Our data strongly suggest all women with endometrioid endometrial cancer should undergo Lynch syndrome screening that includes MMR protein IHC combined with MSI and MLH1 methylation analysis.”
However, the researchers noted that because nonendometrioid and mixed-histology tumors were not evaluated, they were unable to predict the overall benefit of combined IHC, MSI and MLH1 methylation in women with these less common histologies that also occur in women with Lynch syndrome mutations.
“Prospective studies will clarify the utility of IHC, MSI and MLH1 methylation analysis in these patients and in the endometrial cancer population in general,” Goodfellow and colleagues wrote. – by Cameron Kelsall
Disclosure: Goodfellow reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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