Mismatch repair deficiency occurs very rarely in seminomas

Abstract

Background: Dense tumor-associated lymphocyte infiltration is linked to mismatch repair (MMR) deficiency in colorectal and endometrial cancer. MMR deficiency is of high clinical importance as MMR deficient cancers tend to react favorably to treatment with immune checkpoint inhibitors. Strong lymphocytic infiltration is a morphological hallmark of seminomas. We thus asked whether seminomas may exhibit MMR deficiency at relevant frequency.Methods: To screen for tumors with MMR deficiency, protein expression of MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry (IHC) on a tissue microarray (TMA) containing 574 seminomas.Results: In total, 536 cases were evaluable resulting in 481 seminomas with unequivocally intact MMR protein expression. In 55 cancers, one or several IHC stains were equivocal and lacked detectable MMR protein in both tumor and stromal cells. Large section IHC analysis of all 55 equivocal cases demonstrated substantial staining issues due to improper fixation in 54 cases and identified one tumor with clear-cut MLH1 and PMS2 protein loss. This seminoma showed homogeneous loss of MLH1 and PMS2 in the entire tumor mass whereas minor adjacent foci of associated germ cell neoplasia in situ (GCNIS) were MMR intact.Polymerase chain reaction (PCR) analysis using the 5 microsatellite loci of the "Bethesda Panel" revealed instability in 1 of 4 interpretable loci ("MSI-low") and additional instability of the complex tetra-penta repeat locus MYCL1 in this tumor.Conclusions: In summary, one single seminoma with MMR deficiency, characterized by protein loss of MLH1 and PMS2, was identified among 536 interpretable seminomas (0.19%). MMR deficiency is not a relevant determinant of lymphocyte influx in seminoma.

Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors

“…Also, the rate of MMRd in testicular cancers has been reported to be very low, i.e. much less than 1% [34,35]. These observations contrast the relatively high percentage of MMRd in second primary CRC among TC survivors and agree with our finding that second primary MMRd CRC of TC survivors are largely unrelated to Lynch syndrome.…”

Predictive tissue markers in testicular germ cell tumors: Immunohistochemical expression of MLH1 and REV-7 proteins

“…Dum et al studied the immunohistochemical expression of MLH1, PMS2, MSH2 and MSH6 on a tissue microarray, which contained 574 seminomas. They reported MMR deficiency, as evidenced by loss of MLH1 and PMS2 expression, in only one seminoma [ 22 ]. Finally, loss of MLH1 expression could be attributed to epigenetic events, including MLH1 promoter methylation, or germline mutations, such as those met in Lynch syndrome [ 23 , 24 ].…”