Table 2.
Characteristics of the Participants and Their Tumors That Were Included in This Study
| SLS ID | Sex | Age at diagnosis, years | Tumor ID | Tumor type | MMR IHC loss | MSI status | Family cancer history (MMR IHC result) | Clinical criteria | Final classification∗ | Evidence supporting classification |
|---|---|---|---|---|---|---|---|---|---|---|
| C1 | F | 19 | CRC | MSH2/MSH6 | MSI-H | Lynch | MSH2: c.212-478T>G (germline) | |||
| C2 | M | 37 | CRC | MSH2/MSH6 | MSI-H | Lynch | MSH2 deletion of exon 6 (germline) | |||
| SLS1 | F | 52 | T1 | CRC: adenocarcinoma of transverse colon | MLH1/PMS2 | NT | Sister CRC (normal) at 42 years, breast at 53 years | None | Double MLH1 somatic |
MLH1: c.879C>G p.Tyr293Ter (somatic) MLH1: c.1975C>T p.Arg659Ter (somatic) |
| SLS2 | M | 51 | T2A | Kidney | MLH1/PMS2 | NT | None | None | NC | |
| 51 | T2B | Colonic tubular adenoma | Normal | NT | ||||||
| SLS3 | M | 45 | T3 | CRC: adenocarcinoma of transverse colon | MLH1/PMS2 | MSI-H | Sister CRC at 40 years; brother CRC (normal) at 45 years, pancreas at 60 years; brother kidney (normal) at 57 years, prostate at 63 years; brother brain at 59 years | Revised Bethesda | Single MLH1 somatic | MLH1: c.332C>T p.Ala111Val (somatic) |
| SLS4 | F | 68 | T4A | Breast | Normal | MSS | Brother CRC at unknown age; sister CRC at 72 and 77 years; sister CRC (normal) at 67 and CRC (MLH1/PMS2 loss†) at 78 years | None | Double MLH1 somatic | Multiple somatic MLH1 variants including truncating mutation MLH1: c.1036C>T p.Gln346Ter, MMRd not present across all tumors |
| 78 | T4B | Colonic tubulovillous adenoma | MLH1/PMS2 | NT | ||||||
| SLS5 | F | 42 | T5 | CRC: adenocarcinoma of transverse colon | MLH1/PMS2 | MSI-H | Mother CRC at 45 years; father CRC at 54 years | Amsterdam II | Double MLH1 somatic |
MLH1: c.1989+1G>A (somatic) MLH1: LOH (somatic) |
| SLS6 | F | 41 | T6A | CRC | NT | NT | None | Revised Bethesda | Lynch | MLH1: c.1958T>G p.Leu653Arg (germline) |
| 53 | T6B | CRC: adenocarcinoma of transverse colon | MLH1/PMS2 | NT | ||||||
| 53 | T6C | CRC | MLH1/PMS2 | NT | ||||||
| 76 | T6D | Sebaceous carcinoma | MLH1/PMS2 | NT | ||||||
| SLS7 | M | 66 | T7A | CRC: adenocarcinoma of rectum | MSH2/MSH6 | MSI-H | Daughter CRC at 45 years, mesothelioma (normal) at 48 years; sister endometrial at 37 years; brother bladder at 81 years; sister lung at 58 years | Amsterdam II | Double MSH2 somatic | MSH2: c.1351C>T p.Gln451Ter (somatic) |
| 79 | T7B | Colonic tubular adenoma | Normal | NT | MSH2: c.1204C>T p.Gln402Ter (somatic) | |||||
| SLS8 | M | 62 | T8A | Tubulovillous adenoma of rectum | MSH2/MSH6 | MSI-H | Mother CRC at 93 years | None | Double MSH2 somatic | MSH2: c.859G>T p.Gly287Ter (somatic) |
| 62 | T8B | CRC | Normal | NT | MSH2: c.2465_2466delinsAG p.Cys822Ter (somatic) | |||||
| 75 | T8C | Prostate | NT | NT | ||||||
| SLS9‡ | F | 54 | T9A | Duodenum | MSH6 | NT | Daughter ovarian at 40 years and endometrial at 40 years | None | Double MSH2 somatic | Multiple MSH2 somatic mutations, not shared with first-degree relative, MMRd not present across all tumors |
| 58 | T9B | CRC: mucinous adenocarcinoma of ascending colon | MSH2/MSH6 | NT | ||||||
| 67 | T9C | Brain | Normal | NT | ||||||
| SLS10‡ | F | 40 | T10A | Ovary | MSH2/MSH6 | MSI-H | Double MSH2 somatic | Multiple MSH2 somatic mutations, not shared with first-degree relative, mutational signatures 14 and 20 and POLD1 somatic mutation supporting somatic etiology | ||
| 40 | T10B | Endometrium | MSH2/MSH6 | NT | ||||||
| SLS11§ | F | 40 | T11A | CRC: mucinous adenocarcinoma of caecum | MSH2/MSH6 | NT | Daughter CRC at 35 years; brother CRC at 29 years and 46 years; brother CRC at 59 years | Amsterdam I | Lynch | MSH2: 9.5 Mb Inversion ex1-7 (germline) |
| 51 | T11B | Breast | NT | NT | ||||||
| SLS12§ | F | 35 | T12 | CRC: adenocarcinoma of sigmoid colon | MSH2/MSH6 | MSI-H | Lynch | MSH2: 9.5 Mb Inversion ex1-7 (germline) | ||
| SLS13 | F | 41 | T13 | CRC: adenocarcinoma of transverse colon | MSH2/MSH6 | NT | None | Revised Bethesda | Single MSH2 somatic | MSH2: c.2006-3T>G (somatic) |
| SLS14 | F | 66 | T14 | Endometrium | MSH2/MSH6 | NT | Brother CRC at 63 years | none | Double MSH2 somatic |
MSH2: c.1276+2delT (somatic) MSH2: c.2131C>T p.Arg711Ter (somatic) |
Family Cancer History, cancer in first degree relatives only shown; MMR IHC results shown in parentheses.
F, female; M, male; CRC, colorectal cancer; MMR, mismatch repair; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NT, not able to be tested; SLS, suspected Lynch syndrome.
Positive controls. Control 1: intronic mutation disrupting splicing. Control 2: deletion of exon 6 in MSH2.
Final Classification—classification for each SLS case after germline whole-genome sequencing and tumor sequencing analysis detailed in this study. Double and single somatic mutation classification considered to be non-Lynch syndrome and of sporadic etiology. NC, tumor failed testing and therefore no classification could be achieved.
Sister developed two CRCs: one at age 67 years with normal MMR protein expression and one at age 78 years with loss of MLH1/PMS2 protein expression resulting from MLH1 promoter hypermethylation in the tumor.
Relative pair: SLS10 is the daughter of SLS9.
Relative pair: SLS12 is the daughter of SLS11.