Table 5.
Performance Characteristics of Selected Strategies for the Identification of Patients With Lynch Syndrome, According to the Mismatch Repair Gene Mutateda
| Tumor MMR Testing | Germline MMR Gene Mutation | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Sensitivity | Specificity | Positive Predictive Value |
Negative Predictive Value |
||||||
| No./ Total No. |
% (95% CI) |
No./ Total No. |
% (95% CI) |
No./ Total No. |
% (95% CI) |
No./ Total No. |
% (95% CI) |
P Valueb | |
|
MLH1 (n = 3589)c CRC patients fulfilling a condition ≥1 Criterion of revised Bethesda guidelines |
34/34 | 100 (98.5–100) |
3481/3555 | 97.9 (97.4–98.4) |
34/108 | 31.5 (22.2–40.7) |
3481/3481 | 100 (99.9–100) |
<.001 |
| Jerusalem recommendationsd | 32/34 | 94.1 (84.7–100) |
3464/3555 | 97.4 (96.9–97.9) |
32/123 | 26.0 (17.8–34.1) |
3464/3466 | 99.9 (99.8–100) |
<.001 |
| Jerusalem recommendationsd or ≥1 criterion of revised Bethesda guidelines |
34/34 | 100 (98.5–100) |
3424/3555 | 96.3 (95.6–96.8) |
34/165 | 20.6 (14.1–27.0) |
3424/3424 | 100 (99.9–100) |
<.001 |
| Multivariate modele | 28/34 | 82.4 (68–96.6) |
3513/3555 | 98.8 (98.4–99.1) |
28/70 | 40.0 (27.8–52.1) |
3513/3519 | 99.8 (99.6–99.9) |
<.001 |
| Any CRC patient (universal strategy) | 34/34 | 100 (98.5–100) |
3336/3555 | 93.8 (93.0–94.6) |
34/253 | 13.4 (9.0–17.8) |
3336/3336 | 100 (99.9–100) |
[Reference] |
|
MSH2 (n = 3422)c CRC patients fulfilling a condition ≥1 Criterion of revised Bethesda guidelines |
31/33 | 93.9 (84.2–100) |
3366/3389 | 99.3 (99.0–99.6) |
31/54 | 57.4 (43.2–71.5) |
3366/3368 | 99.9 (99.8–100) |
<.001 |
| Jerusalem recommendationsd | 29/33 | 87.9 (75.2–100) |
3361/3389 | 99.2 (98.8–99.4) |
29/57 | 50.9 (37.0–64.7) |
3361/3365 | 99.9 (99.7–100) |
<.001 |
| Jerusalem recommendationsd or ≥1 criterion of revised Bethesda guidelines |
33/33 | 100 (98.4–100) |
3353/3389 | 98.9 (98.5–99.3) |
33/69 | 47.8 (35.3–60.3) |
3353/3353 | 100 (99.9–100) |
<.001 |
| Multivariate modele | 31/33 | 93.9 (84.2–100) |
3370/3389 | 99.4 (99.1–99.6) |
31/50 | 62.0 (47.5–76.4) |
3370/3372 | 99.9 (99.8–100) |
<.001 |
| Any CRC patient | 33/33 | 100 (98.4–100) |
3336/3389 | 98.4 (98.0–98.8) |
33/86 | 38.4 (27.5–49.2) |
3336/3336 | 100 (99.9–100) |
[Reference] |
|
MSH6 (n = 3391)c CRC patients fulfilling a condition ≥1 criterion of revised Bethesda guidelines |
3/9 | 33.3 (0–69.6) |
3362/3382 | 99.4 (99.1–99.6) |
3/23 | 13.0 (0–28.9) |
3362/3368 | 99.8 (99.6–99.9) |
<.001 |
| Jerusalem recommendationsd | 6/9 | 66.7 (30.3–100) |
3359/3382 | 99.3 (99.0–99.6) |
6/29 | 20.7 (4.22–37.1) |
3359/3362 | 99.9 (99.7–100) |
.11 |
| Jerusalem recommendationsd or ≥1 criterion of revised Bethesda guidelines |
7/9 | 77.8 (45.0–100) |
3350/3382 | 99.1 (98.6–99.3) |
7/39 | 17.9 (4.62–31.2) |
3350/3352 | 99.9 (99.8–100) |
.13 |
| Multivariate modele | 5/9 | 55.6 (17.5–93.5) |
3365/3382 | 99.5 (99.2–99.7) |
5/22 | 22.7 (2.94–42.5) |
3365/3369 | 99.9 (99.7–100) |
.02 |
| Any CRC patient | 9/9 | 100 (94.4–100) |
3336/3382 | 98.6 (98.2–99.0) |
9/55 | 16.4 (5.6–27.0) |
3336/3336 | 100 (99.9–100) |
[Reference] |
|
PMS2 (n = 3351)c CRC patients fulfilling a condition ≥1 criterion of revised Bethesda guidelines |
4/6 | 66.7 (20.6–100) |
3342/3345 | 99.9 (99.7–99.9) |
4/7 | 57.1 (13.3–100) |
3342/3344 | 99.9 (99.8–100) |
.30 |
| Jerusalem recommendationsd | 3/6 | 50.0 (1.6–98.3) |
3340/3345 | 99.9 (99.7–100) |
3/8 | 37.5 (0–77.3) |
3340/3343 | 99.9 (99.7–100) |
<.001 |
| Jerusalem recommendationsd or ≥1 criterion of revised Bethesda guidelines |
4/6 | 66.7 (20.6–100) |
3339/3345 | 99.8 (99.6–99.9) |
4/10 | 40.0 (4.64–75.3) |
3339/3341 | 99.9 (99.8–100) |
<.001 |
| Multivariate modele | 3/6 | 50.0 (1.6–98.3) |
3341/3345 | 99.9 (99.7–100) |
3/7 | 42.9 (0–86.6) |
3341/3344 | 99.9 (99.7–100) |
<.001 |
| Any CRC patient | 6/6 | 100 (91.6–100) |
3336/3345 | 99.7 (99.5–99.9) |
6/15 | 40.0 (11.8–68.1) |
3336/3336 | 100 (99.9–100) |
[Reference] |
Abbreviations: CRC, colorectal cancer; MMR, mismatch repair.
a
This analysis was limited to population-based cohorts.
b
With respect to universal strategy (Mathews correlation coefficient comparison).
c
Probands in whom strategies for the identification of germline mutations for each specific MMR gene could be assessed.
d
Age at CRC diagnosis ≤70 years.
e
Defined as fulfillment of ≥1 of the following characteristics: CRC diagnosed at ≤60 years, ≥1 first-degree relative with CRC diagnosed at ≤50 years, or personal history of metachronous Lynch syndrome-related tumors diagnosed at ≤50 years.