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 |
n=124*†¶** | n=23 | n=147 | n=66*¶ | n=15* | n=81 | n=7*§** | n=4§ | 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 |
Tumour location‡ | 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 tumour | 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%) |
The maximum percentage of PREMM5 is >50%.
Three-generation pedigrees were not available for all patients. Ten patients with LS, 23 double somatic (DS) patients and three unexplained patients provided FDR cancer history only.
*Eight Ohio patients with mismatch repair-deficient (dMMR) LS, 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 patients with dMMR LS were excluded from this table due to being first-degree relative pairs (mother–daughter pair and sibling pair). One from each pair was excluded (the proband was retained).
‡Tumours may exceed the number of patients due to synchronous tumours.
§Four Ohio unexplained patients and one Iceland unexplained patient had insufficient material for tumour sequencing and were excluded from this table as it is not known whether they had DS pathogenic variant (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.
LS, Lynch syndrome; TNM, tumour, node, metastases classification.