Tumor Mismatch Repair Immunohistochemistry and DNA MLH1 Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-Level Germline Mismatch Repair Gene Mutation Testing

Abstract

Purpose Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations. Patients and Methods Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS). Results Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered. Conclusion Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.

Efficient Screening Strategy for Lynch Syndrome in Japanese Endometrial Cancer

“…The SGO criteria released in 2007 are being now inspected. The sensitivity of the SGO 5-10% criteria for MMR gene mutation carrier is reportedly to be 85.7-93% (Ryan et al 2012;Buchanan et al 2014). On the other hand, Bruegl et al (2014a) skeptically reported that the sensitivity of the SGO 5-10% criteria for candidates for genetic testing (probable LS with EC) is 32.6%.…”

“…The MSH6 mutation is found more frequently in EC patients than in CRC patients (Hendriks et al 2004). When IHC is performed on the tumors taken from all EC patients, 75-90% of tumors with loss of MLH1 protein expression are sporadic EC with MLH1 gene promoter hypermethylation (Bruegl et al 2014b;Buchanan et al 2014). We performed methylation assays on the 20 tumors with loss of MLH1 alone or MLH1 and PMS2 protein expression.…”

“…If the social environment and medical systems that provide genetic information and support for patients are not properly maintained, the benefits that US can bring to patients will be much less extensive than the theoretical benefits. The third problem is that the positive predictive value of US is lower than those of other screening strategies (Buchanan et al 2014;Ferguson et al 2014), implying that the ratio of patients with suspected LS without germline mutations is relatively high. In the group of suspected LS patients without germline mutations, the incidence of LS-associated cancers is lower than that in the group of LS patients, but significantly higher than that in the general population.…”

“…We believe that the strategy consisting of the APF criteria and molecular analyses leads to more efficient LS screening in EC patients than US and that it enables the implementation of appropriate management. Many studies have indicated that US consisting of IHC and additional methylation assays could select about 10% of all EC patients as suspected LS (Batte et al 2014;Bruegl et al 2014a;Buchanan et al 2014). Using our strategy, we selected 40 (11.1%) of the 360 EC patients as candidates for genetic testing (suspected LS).…”

Update on Hereditary Colorectal Cancer

“…Buchanan et al described family histories of Lynch-like syndrome patients with high incidence of metachronous and synchronous CRC and fulfillment of AC (28). On the other hand, Mas-Moya and colleagues identified significant differences between patients with Lynch-like syndrome and those with Lynch syndrome (29).…”