Clinical Challenges Associated with Universal Screening for Lynch Syndrome–Associated Endometrial Cancer

Abstract

Universal testing for Lynch syndrome is now a routine component of the diagnostic work-up of endometrial cancer patients. The purpose of this study was to identify prospectively the barriers to universal screening based on a tissue testing approach (microsatellite instability analysis, immunohistochemistry for DNA mismatch repair proteins, and MLH1 methylation analysis). Endometrial carcinoma patients (n=213) prospectively underwent microsatellite instability and immunohistochemistry testing for expression of DNA mismatch repair proteins. Patients with low (MSI-L) or high (MSI-H) levels of tumor microsatellite instability or immunohistochemical loss of MLH1 (and absent MLH1 methylation), MSH2, MSH6, or PMS2 were referred to a genetic counselor for consideration of germline testing. Six discordances (3.1% of tested cases) between immunohistochemistry and microsatellite instability were identified. Half of these exhibited heterogeneous immunohistochemical loss of MLH1/PMS2 and were microsatellite stable (MSS). Of the remaining cases, one was MSS with immunohistochemical loss of MSH6, one was MSS with immunohistochemical loss of MLH1/PMS2 and absent MLH1 promoter methylation, and one was MSI-H with intact expression of DNA MMR proteins. Four patients had MSI-L tumors with intact immunohistochemical protein expression; the clinical significance of MSI-L in endometrial cancer is unclear. Eight patients did not have germline mutations despite tissue testing suggesting Lynch syndrome. Including cases with insufficient tissue for testing and patients declining tissue or germline testing, we encountered significant barriers to universal screening in 13.6% of screened patients (29/213) that preclude designation of a tumor as sporadic or hereditary.

Usefulness of immunohistochemistry for mismatch repair protein and microsatellite instability examination in adenocarcinoma and background endometrium of sporadic endometrial cancer cases

“…The rate of MSI-H was 10.2% in our present investigation, that is, lower than the approximately 20% reported in previous studies in Western countries. [10][11][12] Our data suggest that the MSI-H rate in Japanese EC may be intrinsically low, as a similar trend was observed in stomach cancer in Asians. 16 As to IHC, 23.5% of sporadic EC showed loss of some MMR proteins in agreement with prior reports.…”

“…The frequency of MSI-H in sporadic EC is approximately 20% according to western reports. [10][11][12] However, whether the rate is the same in Asians is still uncertain due to lack of data from this region.…”

Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes

“…Indeed, approximately 2-12% of the patients diagnosed with EC are believed to have disease caused by hereditary genetic alterations. [4][5][6][7][8] The most common cause of inherited EC is Lynch syndrome (LS), characterized by the early onset of colorectal and ECs associated with cancers of the ovary, the stomach and the upper urinary and biliary tracts. 9 This highly penetrant and autosomal dominant cancer syndrome is caused by the germline alterations of DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2.…”

Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients

“…49 When compared with MMR IHC 34,37,50 and MSI analysis, 13,36 the sensitivity of detecting LS is equivalent to MSI analysis when using four MMR proteins for IHC. 51 Approximately 3% of the cases were discordant in these two methods, and 5% of cancers that demonstrated MSI had normal MMR protein expression, 52,53 while some tumors with pathogenic variants of g.MSH6 revealed microsatellite stability, 33 like case 3 in the current study (Table 2). IHC is readily available and generally inexpensive and can predict the causative gene; therefore, it is presently considered the optimal first-line screening tool rather than the MSI test.…”