Table 2

Clinical characteristics of patients with double somatic pathogenic variants or unexplained tumours compared with Lynch syndrome

CharacteristicOhio Lynch syndromeIceland Lynch syndromeLynch syndrome combinedOhio double somaticIceland double somaticDouble somatic combinedOhio unexplainedIceland unexplainedUnexplained combined
n=124*†¶**n=23n=147n=66*¶n=15*n=81n=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)
 20–293 (2.4%)03 (2%)1 (1.5%)01 (1.2%)000
 30–3916 (12.9%)1 (4.3%)17 (11.6%)4 (6%)04 (4.9%)01 (25%)1 (9.1%)
 40–4937 (29.8%)2 (8.8%)39 (26.5%)13 (19.7%)1 (6.7%)14 (17.3%)1 (14.3%)01 (9.1%)
 50–5934 (27.4%)6 (26.1%)40 (27.2%)13 (19.7%)4 (26.7%)17 (21%)1 (14.3%)01 (9.1%)
 60–6922 (17.7%)7 (30.4%)29 (19.7%)19 (28.8%)2 (13.3%)21 (25.9%)3 (42.9%)03 (27.3%)
 70–7910 (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%)
 80–892 (1.6%)1 (4.3%)3 (2%)2 (3%)3 (20%)5 (6.2%)1 (14.3%)01 (9.1%)
 90–990001 (1.5%)01 (1.2%)01 (25%)1 (9.1%)
Gender
 Male70 (56.5%)18 (78.3%)88 (59.9%)33 (50%)8 (53.3%)41 (50.6%)7 (100%)1 (25%)8 (72.7%)
 Female54 (43.5%)5 (21.7%)59 (40.1%)33 (50%)7 (46.7%)40 (49.4%)03 (75%)3 (27.3%)
Self-reported race
 Caucasian108 (87.1%)23 (100%)131 (89.1%)60 (90.9%)15 (100%)75 (92.6%)6 (85.7%)4 (100%)10 (90.9%)
 African-American11 (8.8%)011 (7.5%)5 (7.6%)05 (6.2%)1 (14.3%)01 (9.1%)
 Asian4 (3.2%)04 (2.7%)000000
 Other1 (0.8%)01 (0.7%)1 (1.5%)01 (1.2%)000
 Not reported000000000
Tumour location‡n=139n=25n=164n=67n=15n=82n=8n=4n=12
 Right82 (59%)15 (60%)97 (59.1%)51 (76.1%)12 (80%)63 (76.8%)2 (25%)2 (50%)4 (33.3%)
 Left33 (23.7%)7 (28%)40 (24.4%)8 (11.9%)2 (13.3%)10 (12.2%)1 (12.5%)1 (25%)2 (16.7%)
 Rectosigmoid3 (2.2%)03 (1.8%)3 (4.5%)1 (6.7%)4 (4.8%)1 (12.5%)01 (8.3%)
 Rectum21 (15.1%)3 (12%)24 (14.6%)5 (7.5%)05 (6.1%)4 (50%)1 (25%)5 (41.7%)
 Unknown000000000
Stage (TNM)
 I34 (27.4%)4 (17.4%)38 (25.9%)12 (18.2%)1 (6.7%)13 (16%)2 (28.6%)2 (50%)4 (36.4%)
 II37 (29.8%)14 (60.9%)51 (34.7%)28 (42.2%)9 (60%)37 (45.7%)1 (14.3%)2 (50%)3 (27.3%)
 III36 (29%)3 (13%)39 (26.5%)24 (36.4%)4 (26.7%)28 (34.6%)3 (42.9%)03 (27.3%)
 IV12 (9.7%)2 (8.7%)14 (9.5%)2 (3%)02 (2.5%)000
 Unavailable5 (4%)05 (3.4%)01 (6.7%)1 (1.2%)1 (14.3%)01 (9.1%)
Other self-reported malignancy
 Synchronous colon cancer13 (10.5%)2 (8.7%)15 (10.2%)1 (1.5%)01 (1.2%)1 (14.3%)01 (9.1%)
 Metachronous colon cancer15 (12.1%)1 (4.3%)16 (10.9%)0001 (14.3%)01 (9.1%)
 Endometrial cancer13 (10.5%)1 (4.3%)14 (9.5%)1 (1.5%)01 (1.2%)000
 Breast cancer1 (0.8%)01 (0.7%)1 (1.5%)01 (1.2%)01 (25%)1 (9.1%)
 Ovarian cancer000000000
 Stomach cancer2 (1.6%)1 (4.3%)3 (2%)01 (6.7%)1 (1.2%)000
 Small bowel cancer3 (2.4%)03 (2%)000000
 Urinary tract4 (3.2%)1 (4.3%)5 (3.4%)1 (1.5%)2 (13.3%)3 (3.7%)1 (14.3%)01 (9.1%)
 Hepatobiliary tract000000000
 Sebaceous neoplasm4 (3.2%)1 (4.3%)5 (3.4%)000000
 Brain tumour000000000
 Cervical cancer2 (1.6%)02 (1.4%)1 (1.5%)01 (1.2%)000
 Other4 (3.2%)2 (8.7%)6 (4.1%)9 (13.6%)5 (33.3%)14 (17.3%)1 (14.3%)01 (9.1%)
 None77 (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 malignancies42 (33.9%)4 (17.4%)46 (31.3%)3 (4.5%)2 (13.3%)5 (6.2%)2 (28.6%)02 (18.2%)
Clinical criteria
 Amsterdam II32 (25.8%)8 (34.8%)40 (27.2%)1 (1.5%)1 (6.7%)2 (2.5%)000
 Amsterdam II using PREMM5 cancers44 (35.5%)8 (34.8%)52 (35.4%)3 (4.5%)1 (6.7%)4 (4.9%)1 (14.3%)01 (9.1%)
 Revised Bethesda108 (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 EC71 (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.