Table 2.
Clinical Characteristics of patients with double somatic pathogenic variants or unexplained tumors compared to Lynch syndrome
| Characteristic | Ohio Lynch syndrome | Iceland Lynch syndrome | Lynch syndrome combined | Ohio double somatic | Iceland double somatic | Double somatic combined | Ohio unexplained | Iceland unexplained | Unexplained combined |
|---|---|---|---|---|---|---|---|---|---|
| OHIO | n=1241,2,5,6 | n=23 | n=147 | n=6615 | n=151 | n=81 | n=71,4,6 | n=44 | n=11 |
| Age (Average, Range) | 52.4 (20–86) | 62 (31–86) | 53.9 (20–86) | 58.8 (27–96) | 69 (45–88) | 60.7 (27–96) | 65 (44–84) | 69.3 (30–94) | 66.7 (30–94) |
| 20–29 | 3 (2.4%) | 0 | 3 (2%) | 1 (1.5%) | 0 | 1 (1.2%) | 0 | 0 | 0 |
| 30–39 | 16 (12.9%) | 1 (4.3%) | 17 (11.6%) | 4 (6%) | 0 | 4 (4.9%) | 0 | 1 (25%) | 1 (9.1%) |
| 40–49 | 37 (29.8%) | 2 (8.8%) | 39 (26.5%) | 13 (19.7%) | 1 (6.7%) | 14 (17.3%) | 1 (14.3%) | 0 | 1 (9.1%) |
| 50–59 | 34 (27.4%) | 6 (26.1%) | 40 (27.2%) | 13 (19.7%) | 4 (26.7%) | 17 (21%) | 1 (14.3%) | 0 | 1 (9.1%) |
| 60–69 | 22 (17.7%) | 7 (30.4%) | 29 (19.7%) | 19 (28.8%) | 2 (13.3%) | 21 (25.9%) | 3 (42.9%) | 0 | 3 (27.3%) |
| 70–79 | 10 (8.1%) | 6 (26.1%) | 16 (10.9%) | 13 (19.7%) | 5 (33.3%) | 18 (22.2%) | 1 (14.3%) | 2 (50%) | 3 (27.3%) |
| 80–89 | 2 (1.6%) | 1 (4.3%) | 3 (2%) | 2 (3%) | 3 (20%) | 5 (6.2%) | 1 (14.3%) | 0 | 1 (9.1%) |
| 90–99 | 0 | 0 | 0 | 1 (1.5%) | 0 | 1 (1.2%) | 0 | 1 (25%) | 1 (9.1%) |
| Gender | |||||||||
| Male | 70 (56.5%) | 18 (78.3%) | 88 (59.9%) | 33 (50%) | 8 (53.3%) | 41 (50.6%) | 7 (100%) | 1 (25%) | 8 (72.7%) |
| Female | 54 (43.5%) | 5 (21.7%) | 59 (40.1%) | 33 (50%) | 7 (46.7%) | 40 (49.4%) | 0 | 3 (75%) | 3 (27.3%) |
| Self-reported race | |||||||||
| Caucasian | 108 (87.1%) | 23 (100%) | 131 (89.1%) | 60 (90.9%) | 15 (100%) | 75 (92.6%) | 6 (85.7%) | 4 (100%) | 10 (90.9%) |
| African-American | 11 (8.8%) | 0 | 11 (7.5%) | 5 (7.6%) | 0 | 5 (6.2%) | 1 (14.3%) | 0 | 1 (9.1%) |
| Asian | 4 (3.2%) | 0 | 4 (2.7%) | 0 | 0 | 0 | 0 | 0 | 0 |
| Other | 1 (0.8%) | 0 | 1 (0.7%) | 1 (1.5%) | 0 | 1 (1.2%) | 0 | 0 | 0 |
| Not reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Tumor location3 | n=139 | n=25 | n=164 | n=67 | n=15 | n=82 | n=8 | n=4 | n=12 |
| Right | 82 (59%) | 15 (60%) | 97 (59.1%) | 51 (76.1%) | 12 (80%) | 63 (76.8%) | 2 (25%) | 2 (50%) | 4 (33.3%) |
| Left | 33 (23.7%) | 7 (28%) | 40 (24.4%) | 8 (11.9%) | 2 (13.3%) | 10 (12.2%) | 1 (12.5%) | 1 (25%) | 2 (16.7%) |
| Rectosigmoid | 3 (2.2%) | 0 | 3 (1.8%) | 3 (4.5%) | 1 (6.7%) | 4 (4.8%) | 1 (12.5%) | 0 | 1 (8.3%) |
| Rectum | 21 (15.1%) | 3 (12%) | 24 (14.6%) | 5 (7.5%) | 0 | 5 (6.1%) | 4 (50%) | 1 (25%) | 5 (41.7%) |
| Unknown | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage (TNM) | |||||||||
| I | 34 (27.4%) | 4 (17.4%) | 38 (25.9%) | 12 (18.2%) | 1 (6.7%) | 13 (16%) | 2 (28.6%) | 2 (50%) | 4 (36.4%) |
| II | 37 (29.8%) | 14 (60.9%) | 51 (34.7%) | 28 (42.2%) | 9 (60%) | 37 (45.7%) | 1 (14.3%) | 2 (50%) | 3 (27.3%) |
| III | 36 (29%) | 3 (13%) | 39 (26.5%) | 24 (36.4%) | 4 (26.7%) | 28 (34.6%) | 3 (42.9%) | 0 | 3 (27.3%) |
| IV | 12 (9.7%) | 2 (8.7%) | 14 (9.5%) | 2 (3%) | 0 | 2 (2.5%) | 0 | 0 | 0 |
| Unavailable | 5 (4%) | 0 | 5 (3.4%) | 0 | 1 (6.7%) | 1 (1.2%) | 1 (14.3%) | 0 | 1 (9.1%) |
| Other self-reported malignancy | |||||||||
| Synchronous colon cancer | 13 (10.5%) | 2 (8.7%) | 15 (10.2%) | 1 (1.5%) | 0 | 1 (1.2%) | 1 (14.3%) | 0 | 1 (9.1%) |
| Metachronous colon cancer | 15 (12.1%) | 1 (4.3%) | 16 (10.9%) | 0 | 0 | 0 | 1 (14.3%) | 0 | 1 (9.1%) |
| Endometrial cancer | 13 (10.5%) | 1 (4.3%) | 14 (9.5%) | 1 (1.5%) | 0 | 1 (1.2%) | 0 | 0 | 0 |
| Breast cancer | 1 (0.8%) | 0 | 1 (0.7%) | 1 (1.5%) | 0 | 1 (1.2%) | 0 | 1 (25%) | 1 (9.1%) |
| Ovarian cancer | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stomach cancer | 2 (1.6%) | 1 (4.3%) | 3 (2%) | 0 | 1 (6.7%) | 1 (1.2%) | 0 | 0 | 0 |
| Small bowel cancer | 3 (2.4%) | 0 | 3 (2%) | 0 | 0 | 0 | 0 | 0 | 0 |
| Urinary tract | 4 (3.2%) | 1 (4.3%) | 5 (3.4%) | 1 (1.5%) | 2 (13.3%) | 3 (3.7%) | 1 (14.3%) | 0 | 1 (9.1%) |
| Hepatobiliary tract | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Sebaceous neoplasm | 4 (3.2%) | 1 (4.3%) | 5 (3.4%) | 0 | 0 | 0 | 0 | 0 | 0 |
| Brain tumor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Cervical cancer | 2 (1.6%) | 0 | 2 (1.4%) | 1 (1.5%) | 0 | 1 (1.2%) | 0 | 0 | 0 |
| Other | 4 (3.2%) | 2 (8.7%) | 6 (4.1%) | 9 (13.6%) | 5 (33.3%) | 14 (17.3%) | 1 (14.3%) | 0 | 1 (9.1%) |
| None | 77 (62.1%) | 17 (73.9%) | 94 (64%) | 54 (81.8%) | 8 (53.3%) | 62 (76.5%) | 5 (71.4%) | 3 (75%) | 8 (72.7%) |
| ≥2 LS malignancies | 42 (33.9%) | 4 (17.4%) | 46 (31.3%) | 3 (4.5%) | 2 (13.3%) | 5 (6.2%) | 2 (28.6%) | 0 | 2 (18.2%) |
| Clinical Criteria | |||||||||
| Amsterdam II | 32 (25.8%) | 8 (34.8%) | 40 (27.2%) | 1 (1.5%) | 1 (6.7%) | 2 (2.5%) | 0 | 0 | 0 |
| Amsterdam II using PREMM5 cancers | 44 (35.5%) | 8 (34.8%) | 52 (35.4%) | 3 (4.5%) | 1 (6.7%) | 4 (4.9%) | 1 (14.3%) | 0 | 1 (9.1%) |
| Revised Bethesda | 108 (87.1%) | 19 (82.6%) | 127 (86.4%) | 32 (48.5%) | 9 (60%) | 41 (50.6%) | 5 (71.4%) | 2 (50%) | 7 (63.6%) |
| PREMM5 (%) (Median, IQR) | 9.4 (3.9–30.1) | 6 (2.9–16.5) | 9 (3.6–25.7) | 2.45 (1.5–5.4) | 2.2 (1.7–3.7) | 2.4 (1.6–4.7) | 2.3 (1.8–4.2) | 1.5 (1.0–3.6) | 2.0 (1.6–4.2) |
| PREMM5 ≥2.5% | 109 (87.9%) | 18 (78.3%) | 127 (86.4%) | 33 (50%) | 7 (46.7%) | 40 (49.4%) | 3 (42.9%) | 1 (25%) | 4 (36.4%) |
| ≥1 FDRs with CRC or EC | 71 (57.3%) | 14 (60.9%) | 85 (57.8%) | 12 (18.2%) | 6 (40%) | 18 (22.2%) | 1 (14.3%) | 1 (25%) | 2 (18.2%) |
Eight Ohio dMMR LS patients, nine Ohio dMMR DS patients, one Iceland dMMR DS patient, and two Ohio dMMR unexplained patients were excluded from this table due to having germline pathogenic variants in non-MMR genes and potential for phenotype bias
Two Ohio dMMR LS patients were excluded from this table due to being first-degree relative pairs (mother-daughter pair and sibling pair). One from each pair were excluded (the proband was retained).
Tumors may exceed number of patients due to synchronous tumors
Four Ohio unexplained patients and one Iceland unexplained patient had insufficient material for tumor sequencing and were excluded from this table as it is not known whether they had DS PV or were truly unexplained
The patient with a germline PMS2 pathogenic variant and double somatic MSH6 pathogenic variants is included in the Ohio LS column
The patient with a germline MLH1 pathogenic variant and unexplained absence of MSH6 is included in the Ohio LS column
The maximum percentage of PREMM5 is >50%
Three generation pedigrees were not available for all patients. 10 LS patients, 23 DS patients, and 3 unexplained patients provided FDR cancer history only