Clinical features of reported cases with a constitutional MLH1 epimutation
| Case | Sex | Primary carcinoma | Age (years) | Criteria | Tumour features | Relevant family history | Notable features of epimutation | Ref |
| 1 | F | Colon | 25 | BG | MSI, MLH1−, LOH | None | Extensive monoallelic methylation | 8 |
| H166 | F | Colon (Asc) | 38 | BG | MSI, MLH1−, LOH | None | Extensive methylation | 9 |
| Endometrium | 44 | MSI, MLH1−, ROH | ||||||
| H403 | M | Colon (Trans) | 28 | BG | MSI | No FDRs | Extensive methylation | 9 |
| H450 | F | Colon (Asc) | 23 | BG | NA | No FDRs | Extensive methylation | 9 |
| H628 | M | Colon (Desc) | 17 | BG | NA | No FDRs | Extensive methylation | 9 |
| Colon (Asc) | 29 | MSI, MLH1− | ||||||
| VT | F | Caecum | 46 | BG | MSI, MLH1−, LOH | Mother, colon 64 years | Monoallelic methylation with some mosaicism | 10 |
| Endometrium | 53 | MSI, MLH1−, ROH | ||||||
| Melanoma | 57 | NA | ||||||
| Breast (infiltrating duct) | 63 | MSI, MLH1−, LOH | ||||||
| TT | M | Caecum | 43 | BG | MSI, MLH1−, LOH | Mother, endometrium 55 years | Monoallelic methylation with some mosaicism. No methylation in spermatozoa. | 10, 49 |
| Colon (Desc) | 44 | NA | ||||||
| Duodenum (sync) | 51 | MSI, MLH1−, LOH | ||||||
| Ampulla of Vater | 59 | MSI, MLH1−, LOH | ||||||
| ST | M | Colon | 39 | BG | MSI, MLH1−, LOH | None | Extensive methylation arising de novo on maternal allele. Complete allelic inactivation. | 11 |
| A | F | Endometrium | 45 | BG | MSI, MLH1− | No FH. Epimutation transmitted to son (unaffected at age 48 years) in non-Mendelian pattern | Extensive monoallelic methylation in proband and methylation of maternal allele in son. Complete allelic inactivation in both. No methylation, plus allelic reactivation in spermatozoa of son. | 12 |
| Colon (Asc) | 59 | MSI, MLH1−, L724W* | ||||||
| Rectum, | 60 | MSI, MLH1−, S108R* | ||||||
| Skin sarcoma | 68 | MSI, MLH1− | ||||||
| B | F | Colon | 41 | BG | MSI, MLH1− | None | De novo methylation of maternal allele. Complete allelic inactivation. | 12 |
| Rectum | 45 | MSI, MLH1− | ||||||
| 2 | M | Epidermoid (lip) | 34 | NA | None | De novo methylation (parental allele NI) | 13 | |
| Colon | 35 | BG | MSI, MLH1−, LOH | |||||
| 1 | M | Colon (Asc) | 33 | BG | MSI, MLH1−, BRAF WT | Brother, gastric 51 years | Extensive methylation | 14 |
| Colon (Sig) and rectum | 47, 47 | |||||||
| 2 | F | Colon (Sig) | 58 | BG | MSI, MLH1−, BRAF WT | Son, hyperplastic polyp 34 years | Extensive methylation | 14 |
| Colon (Trans) | 59 | MSI, MLH1−, BRAF WT | ||||||
| 3 | M | Rectum | 41 | BG | MSI, MLH1−, BRAF WT | Mother, colon 59 years; brother, polyps 44 years | Some mosaicism | 14 |
| 4 | M | Colon (Trans) | 39 | BG | MSI, MLH1−, BRAF WT | Mother unaffected at 64 years | Maternally inherited, mosaic in mother & proband | 14 |
| 5 | F | Rectum | 40 | BG | MSI, MLH1− | Mother, cervical 33 years, colon 64 years (MSS, MLH1+) | Extensive monoallelic methylation arising de novo on maternal allele | 14 |
| Colon (Sig) | 41 | |||||||
| 6 | M | Colon (Asc) | 40 | BG | MSI, MLH1− | Father, polyps 50 years | Extensive monoallelic methylation. | 14 |
| Rectum | 44 | |||||||
| 7 | M | Colon (Trans) | 33 | BG | MSI, MLH1− | None | Extensive monoallelic methylation. | 14 |
| 8 | M | Colon (Asc) | 35 | BG | MSI, MLH1− | No FDR | Mosaic. Partial allelic silencing demonstrated. | 14 |
| Skin | 42, 48 | |||||||
| Cyst, sebaceous gland | 49 | |||||||
| 9 | F | Colon (Asc) | 37 | BG | MSI, MLH1− | Father, renal 41 years | De novo on maternal allele, some mosaicism | 14 |
| 10 | F | Colon (left flexure) | 30 | BG | MSI, MLH1− | None | Extensive monoallelic methylation. | 14 |
| 11 | M | Colon (Asc and Trans) | 46, 46 | BG | MSI, MLH1− | None | Some mosaicism | 14 |
| 12 | F | Colon (Asc) | 35 | BG | MSI, MLH1−, BRAF WT | None | Some mosaicism | 14 |
| (H10) | M | Colorectal | 41 | BG | MSI, MLH1− | None | Unconfirmed extensive methylation by MSP | 46 |
| (H29) | F | Colorectal | 37 | Am I | MSI, MLH1− | Positive FH, unspecified | Unconfirmed extensive methylation by MSP | 46 |
| (H32) | M | Colorectal | 51 | Am I | MSI, MLH1+ | Positive FH, unspecified | Unconfirmed partial methylation by MSP | 46 |
| (H42) | M | Colorectal | 65 | Am I | MSI, NA | Positive FH, unspecified | Unconfirmed partial methylation by MSP | 46 |
| (H46)† | M | Colorectal | 48 | Am I | MSI, MLH1+ | Positive FH, unspecified | Unconfirmed partial methylation by MSP | 46† |
| N2 | F | Colon | 35 | BG | MSI, MLH1−, ROH | Extensive hemiallelic methylation. Complete allelic inactivation. | 15 | |
| Endometrium | 45 | |||||||
| F36 | F | Colon | 22, 45 | MSI, MLH1− | Linked 6.4kb deletion from 68bp upstream of ATG start site to intron 2. Complete allelic inactivation. | 15 | ||
| Endometrium | 40 |
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Am, Amsterdam criteria; Asc, ascending; BG, Bethesda guidelines; C, criterion within specified clinical guidelines; Desc, descending; F, female; FDRs, first degree relatives; FH, family history; IHC, immunohistochemistry; LOH, loss of heterozygosity; M, male; Mod, modified; MSI, microsatellite unstable; MSP, methylation specific; MSS, microsatellite stable; NA, not available for study; Rev, revised; ROH, retention of heterozygosity; Sig, sigmoid; Sync, synchronous; Trans, transverse; WT, wild-type.
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Clinical, tumour and molecular features are summarised for cases with a constitutional MLH1 epimutation in chronological order as identified. Cases in parentheses are currently unconfirmed.
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Analyses of tumours for MLH1 expression and the nature of the second hit was not assessed in some cases due to the lack of available specimen.
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*Unpublished data.
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†Personal communication with the authors.
