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Table 3 Summary of the categorization of the SLS tumors, overall and by tumor type, based on the results from tumor panel sequencing, MLH1 methylation and DNA mismatch repair (MMR) immunohistochemistry (IHC) results

From: A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome

Category

CRC

EC

SST

Total

Total tumors tested

80

33

24

137

Resolved

 dMMR-DS—Double somatic MMR mutations

56 (70%)a

15 (45.5%)

17 (70.8%)

88 (64.2%)

 dMMR-MLH1me—MLH1 methylatedb

9 (11.3%)

9 (27.3%)

0 (0%)

18 (13.1%)

 dMMR-PriEpi—Primary MLH1 epimutation

1 (1.2%)

0 (0%)

2 (8.3%)

3 (2.2%)e

 dMMR-LS—Lynch syndrome

1 (1.2%)c

1 (3%)d

0 (0%)

2 (1.5%)

 pMMR—MMR-proficient

7 (8.8%)

1 (3%)

0 (0%)

8 (5.8%)

 Total resolved

74/80 (92.5%)

26/33 (78.8%)

19/24 (79.2%)

119/137 (86.9%)

Unresolved

 dMMR-SS—Single somatic mutation

3 (3.8%)

4 (12.1%)

3 (12.5%)

10 (7.3%)

 dMMR-SLS—remain as SLS

3 (3.8%)

3 (9.1%)

2 (8.3%)

8 (5.8%)

  1. CRC colorectal cancer, EC endometrial cancer, SST sebaceous skin tumor, SLS suspected Lynch syndrome, MMR DNA mismatch repair, dMMR DNA mismatch repair deficient, pMMR DNA mismatch repair proficient, dMMR-DS DNA mismatch repair deficient tumor with double somatic mutations, dMMR-MLH1me DNA mismatch repair deficient tumor presenting with MLH1 methylation, dMMR-PriEpi DNA mismatch repair deficient tumor with a primary MLH1 epimuation, dMMR-LS DNA mismatch repair deficient tumor with a germline pathogenic variant, dMMR-SS DNA mismatch repair deficient tumor with a single somatic mutation, dMMR-SLS mismatch repair deficient tumor with no somatic mutations. Numbers in bold reflect total number of resolved cases by tissue type and overall
  2. aOne tumor carried double somatic mutations in MLH1 and double somatic mutations in MSH6 presenting with loss of all four MMR proteins by IHC
  3. bAll tumors positive for tumor MLH1 methylation demonstrated loss of MLH1/PMS2 by MMR IHC except for one CRC tumor showing solitary PMS2 loss by MMR IHC (confirmed by internal testing)
  4. cThis person carried a germline pathogenic variant in MSH2 (known prior to entering the study) with a somatic MSH2 mutation (2nd hit) and was also positive for tumor MLH1 methylation which accounted for the loss of all four MMR protein expression by IHC
  5. dThis person carried a germline pathogenic variant in MSH6 (missed by prior clinical testing) with a somatic MSH6 mutation (2nd hit) as well as presenting with tumor MLH1 methylation accounting for the observed pattern of loss MLH1/PMS2 and MSH6 by MMR IHC
  6. eTwo people identified as MLH1 epimutation carriers with one carrier developing an SST and the other developed a CRC and an SST
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Journal of Translational Medicine

ISSN: 1479-5876

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