Table 1.
Clinical, Pathological, and Molecular Characteristics of 680 CRC Individuals Who Were Examined in the Discovery Set
| Characteristica | All Individuals (n = 680) |
Mutations in Known CRC-Susceptibility Genes (High Penetrance)b,c |
pd |
Mutations in Known CRC-Susceptibility Genes (Low Penetrance)c,e |
pd |
Mutations in DNA-Repair Genesc,f |
pd |
Mutations in the Homologous Recombination Pathwayc,g |
pd |
Mutations in ATMc |
pd |
Mutations in PALB2c |
pd | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Absent (n = 616) | Present (n = 12) | Absent (n = 616) | Present (n = 19) | Absent (n = 616) | Present (n = 33) | Absent (n = 616) | Present (n = 19) | Absent (n = 616) | Present (n = 5) | Absent (n = 616) | Present (n = 3) | |||||||||
| Sex | female | 414 (61%) | 376 (61%) | 7 (58%) | 0.99 | 376 (61%) | 9 (47%) | 0.24 | 376 (61%) | 22 (67%) | 0.59 | 376 (61%) | 11 (58%) | 0.81 | 376 (61%) | 4 (80%) | 0.65 | 376 (61%) | 1 (33%) | 0.56 |
| male | 266 (39%) | 240 (39%) | 5 (42%) | 240 (39%) | 10 (53%) | 240 (39%) | 11 (33%) | 240 (39%) | 8 (42%) | 240 (39%) | 1 (20%) | 240 (39%) | 2 (67%) | |||||||
| Age of presentation | mean ± SD (years) | 68.8 ± 10.3 | 68.9 ± 10.2 | 58.4 ± 13.8 | 0.0005 | 68.9 ± 10.2 | 72.2 ± 6.2 | 0.16 | 68.9 ± 10.2 | 69.7 ± 10.8 | 0.66 | 68.9 ± 10.2 | 68.2 ± 10.4 | 0.77 | 68.9 ± 10.2 | 75.6 ± 6.6 | 0.14 | 68.9 ± 10.2 | 64.7 ± 18.8 | 0.47 |
| missing | 12 | 12 | 0 | 12 | 0 | 12 | 0 | 12 | 0 | 12 | 0 | 12 | 0 | |||||||
| Race or ethnicity | white | 667 (98%) | 604 (98%) | 12 (100%) | 0.99 | 604 (98%) | 19 (100%) | 0.99 | 604 (98%) | 32 (97%) | 0.50 | 604 (98%) | 18 (95%) | 0.33 | 604 (98%) | 4 (80%) | 0.10 | 604 (98%) | 3 (100%) | 0.99 |
| black | 13 (1.9%) | 12 (2.0%) | 0 | 12 (2.0%) | 0 | 12 (2.0%) | 1 (3.0%) | 12 (2.0%) | 1 (5.3%) | 12 (2.0%) | 1 (20%) | 12 (2.0%) | 0 | |||||||
| Ashkenazi Jewish | no | 155 (86%) | 144 (88%) | 2 (100%) | 0.99 | 144 (88%) | 3 (38%) | 0.0015 | 144 (88%) | 6 (86%) | 0.59 | 144 (88%) | 4 (100%) | 0.99 | 144 (88%) | 1 (100%) | 0.99 | 144 (88%) | 1 (100%) | 0.99 |
| yes | 25 (14%) | 19 (12%) | 0 | 19 (12%) | 5 (62%) | 19 (12%) | 1 (14%) | 19 (12%) | 0 | 19 (12%) | 0 | 19 (12%) | 0 | |||||||
| missing | 500 | 453 | 10 | 453 | 11 | 453 | 26 | 453 | 15 | 453 | 4 | 453 | 2 | |||||||
| Family history of colorectal cancer in first-degree relative(s) | absent | 501 (75%) | 461 (76%) | 8 (73%) | 0.73 | 461 (76%) | 11 (61%) | 0.16 | 461 (76%) | 21 (64%) | 0.099 | 461 (76%) | 12 (63%) | 0.18 | 461 (76%) | 3 (60%) | 0.34 | 461 (76%) | 2 (67%) | 0.55 |
| present | 164 (25%) | 142 (24%) | 3 (27%) | 142 (24%) | 7 (39%) | 142 (24%) | 12 (36%) | 142 (24%) | 7 (37%) | 142 (24%) | 2 (40%) | 142 (24%) | 1 (33%) | |||||||
| missing | 15 | 13 | 1 | 13 | 1 | 13 | 0 | 13 | 0 | 13 | 0 | 13 | 0 | |||||||
| Family history of breast cancer in first-degree relative(s) | absent | 359 (81%) | 329 (82%) | 4 (50%) | 0.044 | 329 (82%) | 9 (90%) | 0.99 | 329 (82%) | 17 (71%) | 0.18 | 329 (82%) | 9 (69%) | 0.27 | 329 (82%) | 3 (75%) | 0.55 | 329 (82%) | 2 (100%) | 0.99 |
| present | 85 (19%) | 73 (18%) | 4 (50%) | 73 (18%) | 1 (10%) | 73 (18%) | 7 (29%) | 73 (18%) | 4 (31%) | 73 (18%) | 1 (25%) | 73 (18%) | 0 | |||||||
| missing | 236 | 214 | 4 | 214 | 9 | 214 | 9 | 214 | 6 | 214 | 1 | 214 | 1 | |||||||
| Family history of ovarian cancer in first-degree relative(s) | absent | 425 (96%) | 384 (96%) | 8 (100%) | 0.99 | 384 (96%) | 10 (100%) | 0.99 | 384 (96%) | 23 (96%) | 0.99 | 384 (96%) | 13 (100%) | 0.99 | 384 (96%) | 4 (100%) | 0.99 | 384 (96%) | 2 (100%) | 0.99 |
| present | 19 (4.3%) | 18 (4.5%) | 0 | 18 (4.5%) | 0 | 18 (4.5%) | 1 (4.2%) | 18 (4.5%) | 0 | 18 (4.5%) | 0 | 18 (4.5%) | 0 | |||||||
| missing | 236 | 214 | 4 | 214 | 9 | 214 | 9 | 214 | 6 | 214 | 1 | 214 | 1 | |||||||
| Family history of any cancer in first-degree relative(s) | absent | 270 (41%) | 249 (41%) | 3 (27%) | 0.54 | 249 (41%) | 6 (33%) | 0.63 | 249 (41%) | 12 (36%) | 0.72 | 249 (41%) | 7 (37%) | 0.81 | 249 (41%) | 2 (40%) | 0.99 | 249 (41%) | 2 (67%) | 0.57 |
| present | 395 (59%) | 354 (59%) | 8 (73%) | 354 (59%) | 12 (67%) | 354 (59%) | 21 (64%) | 354 (59%) | 12 (63%) | 354 (59%) | 3 (60%) | 354 (59%) | 1 (33%) | |||||||
| missing | 15 | 13 | 1 | 13 | 1 | 13 | 0 | 13 | 0 | 13 | 0 | 13 | 0 | |||||||
| Tumor locationh | cecum | 129 (19%) | 117 (19%) | 1 (9.1%) | 0.48 | 117 (19%) | 1 (5.6%) | 0.34 | 117 (19%) | 10 (30%) | 0.31 | 117 (19%) | 7 (37%) | 0.18 | 117 (19%) | 2 (40%) | 0.31 | 117 (19%) | 1 (33%) | 0.062 |
| ascending to transverse colon | 202 (30%) | 184 (30%) | 2 (18%) | 184 (30%) | 5 (28%) | 184 (30%) | 11 (33%) | 184 (30%) | 4 (21%) | 184 (30%) | 2 (40%) | 184 (30%) | 0 | |||||||
| splenic flexure to sigmoid colon | 201 (30%) | 183 (30%) | 6 (55%) | 183 (30%) | 6 (33%) | 183 (30%) | 6 (18%) | 183 (30%) | 3 (16%) | 183 (30%) | 0 | 183 (30%) | 0 | |||||||
| rectum | 136 (20%) | 122 (20%) | 2 (18%) | 122 (20%) | 6 (33%) | 122 (20%) | 6 (18%) | 122 (20%) | 5 (26%) | 122 (20%) | 1 (20%) | 122 (20%) | 2 (67%) | |||||||
| missing | 12 | 10 | 1 | 10 | 1 | 10 | 0 | 10 | 0 | 10 | 0 | 10 | 0 | |||||||
| Tumor differentiation | well to moderate | 534 (90%) | 483 (90%) | 6 (67%) | 0.062 | 483 (90%) | 17 (100%) | 0.40 | 483 (90%) | 28 (90%) | 0.99 | 483 (90%) | 17 (94%) | 0.99 | 483 (90%) | 5 (100%) | 0.99 | 483 (90%) | 1 (50%) | 0.20 |
| poor | 62 (10%) | 56 (10%) | 3 (33%) | 56 (10%) | 0 | 56 (10%) | 3 (9.7%) | 56 (10%) | 1 (5.6%) | 56 (10%) | 0 | 56 (10%) | 1 (50%) | |||||||
| missing | 84 | 77 | 3 | 77 | 2 | 77 | 2 | 77 | 1 | 77 | 0 | 77 | 1 | |||||||
| AJCC disease stage | I | 148 (24%) | 135 (24%) | 4 (40%) | 0.35 | 135 (24%) | 1 (5.9%) | 0.020 | 135 (24%) | 8 (25%) | 0.74 | 135 (24%) | 3 (16%) | 0.40 | 135 (24%) | 0 | 0.051 | 135 (24%) | 0 | 0.88 |
| II | 188 (30%) | 171 (30%) | 1 (10%) | 171 (30%) | 8 (47%) | 171 (30%) | 8 (25%) | 171 (30%) | 4 (21%) | 171 (30%) | 0 | 171 (30%) | 1 (33%) | |||||||
| III | 177 (28%) | 157 (28%) | 4 (40%) | 157 (28%) | 8 (47%) | 157 (28%) | 8 (25%) | 157 (28%) | 6 (32%) | 157 (28%) | 3 (60%) | 157 (28%) | 1 (33%) | |||||||
| IV | 110 (18%) | 101 (18%) | 1 (10%) | 101 (18%) | 0 | 101 (18%) | 8 (25%) | 101 (18%) | 6 (32%) | 101 (18%) | 2 (40%) | 101 (18%) | 1 (33%) | |||||||
| missing | 57 | 52 | 2 | 52 | 2 | 52 | 1 | 52 | 0 | 52 | 0 | 52 | 0 | |||||||
| MSI status | MSS or MSI-low | 475 (84%) | 428 (84%) | 5 (62%) | 0.13 | 428 (84%) | 16 (89%) | 0.75 | 428 (84%) | 26 (87%) | 0.80 | 428 (84%) | 16 (94%) | 0.50 | 428 (84%) | 5 (100%) | 0.99 | 428 (84%) | 2 (100%) | 0.99 |
| MSI-high | 92 (16%) | 83 (16%) | 3 (38%) | 83 (16%) | 2 (11%) | 83 (16%) | 4 (13%) | 83 (16%) | 1 (5.9%) | 83 (16%) | 0 | 83 (16%) | 0 | |||||||
| missing | 113 | 105 | 4 | 105 | 1 | 105 | 3 | 105 | 2 | 105 | 0 | 105 | 1 | |||||||
| CIMP status | CIMP-low or -negative | 382 (80%) | 342 (79%) | 5 (83%) | 0.99 | 342 (79%) | 13 (87%) | 0.75 | 342 (79%) | 22 (88%) | 0.44 | 342 (79%) | 12 (86%) | 0.74 | 342 (79%) | 4 (100%) | 0.59 | 342 (79%) | 1 (100%) | 0.99 |
| CIMP-high | 95 (20%) | 89 (21%) | 1 (17%) | 89 (21%) | 2 (13%) | 89 (21%) | 3 (12%) | 89 (21%) | 2 (14%) | 89 (21%) | 0 | 89 (21%) | 0 | |||||||
| missing | 203 | 185 | 6 | 185 | 4 | 185 | 8 | 185 | 5 | 185 | 1 | 185 | 2 | |||||||
Abbreviations are as follows: AJCC, American Joint Committee on Cancer; CIMP, CpG island methylator phenotype-specific promoter; MSI, microsatellite instability; MSS, microsatellite stable; and SD, standard deviation.
Percentage indicates the proportion of individuals with a specific clinical, pathological, or molecular characteristic in all cases or in strata of germline pathogenic mutations.
High-penetrance CRC-risk genes include APC (excluding c.3920T>A [p.Ile1307Lys]), BMPR1A, CHEK2, MLH1, MSH2, MSH6, MUTYH (biallelic inactivation), PMS2, POLD1, POLE, PTEN, SMAD4, STK11, and TP53.
Individuals who had mutations in the other CRC-risk genes or DNA-repair genes (DRGs) were excluded.
To compare characteristics between subgroups according to the germline mutation status, we used Fisher’s exact test for categorical variables and unpaired t tests for continuous variables.
Low-penetrance CRC-risk mutations include APC c.3920T>A (p.Ile1307Lys) and monoallelic inactivation of MUTYH.
This gene set includes the 40 DRGs listed in Table S2.
Homologous recombination (HR) DRGs included in this analysis are ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11, NBN, PALB2, RAD51, RAD51C, RAD51D, RAD54L, and XRCC3.
One individual who had two lesions (cecum and sigmoid colon) was excluded from the analysis.