Comparison of screening strategies for Lynch syndrome in patients with newly diagnosed endometrial cancer: a prospective cohort study in China

Xiaopei Chao, Lei Li, Ming Wu, Shuiqing Ma, Xianjie Tan, Sen Zhong, Yalan Bi, Jinghe Lang, Xiaopei Chao, Lei Li, Ming Wu, Shuiqing Ma, Xianjie Tan, Sen Zhong, Yalan Bi, Jinghe Lang

Abstract

Background: The prevalence of Lynch syndrome and screening strategies for this disorder in Chinese patients with endometrial cancer have seldom been investigated. Such data would be essential for the screening, prevention, genetic counseling, and treatment of Lynch syndrome. The purpose of this prospective study was to determine the accuracy of the mismatch repair (MMR) protein immunohistochemistry (IHC), microsatellite instability (MSI) test, and clinical diagnostic criteria in screening for Lynch syndrome-associated endometrial cancer (LS-EC) in a prospective Chinese cohort.

Methods: All patients with newly diagnosed endometrial cancer (EC) were evaluated using clinical diagnostic criteria (Amsterdam II criteria and the revised Bethesda guidelines), MSI test, and IHC of MMR proteins in tumor tissues. For all patients, the screening results were compared with results of germline sequencing for pathogenic variants of MMR genes.

Results: Between December 2017 and August 2018, a total of 111 unselected patients with newly diagnosed EC were enrolled. Six patients (5.4%) harbored a pathogenic germline mutation of MMR genes: 1 had a mutation in MutL homolog 1 (MLH1), 2 in MutS homolog 2 (MSH2), and 3 in MutS homolog 6 (MSH6). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for identifying LS-EC were 33.3%, 88.6%, 14.3%, and 95.9%, for the clinical criteria, 66.7%, 75.0%, 14.3%, and 97.3% for IHC of MMR proteins, 100%, 89.9%, 33.3%, and 100% for MSI test, and 100%, 72.4%, 20.0% and 100% for combined IHC and MSI test, respectively. The combination of IHC and MSI test had higher sensitivity and PPV than the clinical criteria (p = 0.030). MSI test and IHC were highly concordant for LS-EC screening (73/77, 94.8%).

Conclusion: The accuracy of the combination of IHC of MMR proteins and MSI test for screening LS among Chinese patients with EC was superior to that of the clinical criteria. Trial registration NCT03291106. Registered on September 25, 2017.

Keywords: DNA mismatch repair genes; Endometrial carcinoma; Germline mutations; Immunohistochemistry; Lynch syndrome; Microsatellite instability.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
A flow diagram of the study. IHC: immunohistochemistry; MMR: mismatch repair; MLH1: MutL homolog 1; PMS2: PMS1 homolog 2; MSH2: MutS homolog 2; MSH6: MutS homolog 6; MSI: microsatellite instability; MSI-H: high-frequency MSI; MSS: microsatellite stable
Fig. 2
Fig. 2
An example of immunohistochemistry (IHC) of mismatch repair (MMR) proteins from Case 4 in Table 2. This patient was 53 years at diagnosis and was confirmed to have grade 1 stage IA uterine endometrioid carcinoma. Two years before the diagnosis of endometrial cancer, she was diagnosed with early-stage colon cancer. Her father and daughter had a history of colon cancer and small intestine cancer, respectively. a Deficient expression of MutL homolog 1 (MLH1) protein in tumor tissues. The cytoplasm of almost all cancer cells had no staining in brown. b Normal expression of MutS homolog 2 (MSH2) protein in tumor tissues. The cytoplasm of cancer cells had homogeneous brown staining. c Normal expression of MutS homolog 6 (MSH6) protein in tumor tissues. The cytoplasm of cancer cells had homogeneous brown staining. d Deficient expression of PMS1 homolog 2 (PMS2) protein in tumor tissues. The cytoplasm of all cancer cells had no staining in brown
Fig. 3
Fig. 3
An example of MSI-H of Case 4 in Table 2. The introduction of this patient refers to the legend of Fig. 2. Electropherogram shows an allelic profile generated from a normal sample (a, b) or from a matching MSH6-deficient tumor sample (c, d) using the MSI detection kit. First, the sex-determination site Amel and the pentanucleotide markers Penta C and Penta D were analyzed. The Amel site and Penta C/Penta D were used to confirm that the tumor sample and the corresponding normal sample were from the same individual. Alleles found in the normal sample should also be present in the tumor sample; otherwise, there may be sample mixing or contamination. In this case, it is advisable to re-extract the sample for testing. The control sample (paraffin-embedded paracancerous tissue) is microsatellite stable (MSS). In this paraffin-embedded tumor tissue (d), a new allele appears compared to the normal sample (b) (new allele peak indicated by the arrow), that is, the mononucleotide repeat markers are unstable. Finally, the results were interpreted by comparing the numbers of changes in the mononucleotide repeat markers in the test samples. Note that additional pentanucleotide alleles of Penta C and Penta D may be present in some MSI-H samples (additional allele peaks indicated by the box are detailed in d)

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