Journal of Surgery Concepts & Practice ›› 2024, Vol. 29 ›› Issue (02): 148-155.doi: 10.16139/j.1007-9610.2024.02.10
• Original article • Previous Articles Next Articles
ZHU Huia, CAI Jidongb,*, LI Minghanc, YANG Wentaoc(
), XU Yec
Received:2024-02-24
Online:2024-03-25
Published:2024-07-01
Contact:
YANG Wentao
E-mail:yangwt97@163.com
CLC Number:
ZHU Hui, CAI Jidong, LI Minghan, YANG Wentao, XU Ye. Consistency analysis of mismatch repair protein expression and microsatellite stability in colorectal cancer[J]. Journal of Surgery Concepts & Practice, 2024, 29(02): 148-155.
Tab 1
Clinical characteristics of CRC with microsatellite status detected by IHC and NGS [n(%)/M(Q1-Q3)]
| Clinical Characteristics | 总计 (n=2 196) | IHC | P value | NGS | P value | ||||
|---|---|---|---|---|---|---|---|---|---|
| pMMR (n=2 069) | dMMR(n=127) | χ2 value | MSI-H (n=139) | MSS (n=2 057) | χ2 value | ||||
| Gender | |||||||||
| Male | 1 313 (59.79) | 1 234 (59.64) | 79(62.20) | 0.326 8 | 0.567 6 | 83 (59.71) | 1 230 (59.80) | 0.000 4 | 0.984 5 |
| Female | 883 (40.21) | 835 (40.36) | 48 (37.80) | 56 (40.29) | 827 (40.20) | ||||
| Age | |||||||||
| mAge（range） | 61 (20-93) | 61 (21-93) | 55 (20.88) | 55 (20-88) | 61 (21-93) | ||||
| ≤60 | 1 075 (48.95) | 999 (48.28) | 76 (59.84) | 6.396 9 | 0.011 | 82 (58.99) | 993 (48.27) | 5.986 1 | 0.014 4 |
| >60 | 1 121 (51.05) | 1 070 (51.72) | 51 (40.16) | 57 (41.01) | 1 064 (51.73) | ||||
| Primary site | |||||||||
| Left | 1 625 (74.00) | 1 583 (76.51) | 42 (33.07) | 117.348 0 | <0.01 | 47 (33.81) | 1 578 (76.71) | 124.543 0 | <0.01 |
| Right | 571 (26.00) | 486 (23.49) | 85 (66.93) | 92 (66.19) | 479 (23.29) | ||||
| AJCC | |||||||||
| Ⅰ-Ⅲ | 1 645 (74.91) | 1 529 (73.90) | 116 (91.34) | 19.358 9 | <0.01 | 125 (89.93) | 1 520 (73.89) | 17.804 9 | <0.01 |
| Ⅳ | 551 (25.09) | 540 (26.10) | 11 (8.66) | 14 (10.07) | 537 (26.11) | ||||
| Differentiation | |||||||||
| Well | 39 (1.78) | 36 (1.74) | 3 (2.36) | 19.070 3 | <0.01 | 1 (0.72) | 38 (1.85) | 19.160 6 | <0.01 |
| Medium | 1 476 (67.21) | 1 413 (68.29) | 63 (49.61) | 72 (51.80) | 1 404 (68.25) | ||||
| Low | 681 (31.01) | 620 (29.97) | 61 (48.03) | 66 (47.48) | 615 (29.90) | ||||
Tab 2
Expression of MMR proteins detected by IHC [n (%)]
| MMR | MLH1 | MSH2 | MSH6 | PMS2 | n (%) |
|---|---|---|---|---|---|
| Expression of MMR proteins | （-） | （+） | （+） | （-） | 77 (60.63) |
| （+） | （-） | （-） | （+） | 23 (18.11) | |
| （+） | （+） | （+） | （-） | 15 (11.81) | |
| （+） | （-） | （+） | （+） | 4 (3.15) | |
| （+） | （+） | （-） | （+） | 3 (2.36) | |
| （+） | （+） | （-） | （-） | 2 (1.57) | |
| （-） | （+） | （+） | （+） | 1 (0.79) | |
| （-） | （+） | （-） | （-） | 1 (0.79) |
Tab 3
Germline mutations in MMR genes in MSI-H subgroup detected by NGS [n (%)]
| Type of causation | Pathogenic variants | Likely pathogenic variants | |||
|---|---|---|---|---|---|
| MMR | n (%) | Type of variation | n (%) | Type of variation | |
| MLH1 | 9 (26.47) | Missense mutation×3, non-frameshift deletion×2, Frame shift missing×1, frame shift insertion×1，splice×1, intron×1 | 6 (17.65) | Frameshift missing×3, complex mutation×1，missense mutation×1，splice×1 | |
| MSH2 | 4 (11.76) | Frameshift missing×3 Splice×1 | 5 (14.71) | Frameshift insertion×2 Frameshift missing×3 | |
| MSH6 | 3 (8.82) | Stop×2 Frame shift insertion×1 | 1 (2.94) | Frame shift insertion×1 | |
| PMS2 | 1 (2.94) | Stop×1 | 5 (14.71) | Frameshift missing×2, Stop×1, Frameshift insertion×1 | |
| Total | 17 (50.00) | 17 (50.00) | |||
Tab 4
Discrepancy in microsatellite status detected by IHC and NGS [n (%)]
| MSI-status | MSI-H | MSS | Total |
|---|---|---|---|
| pMMR | 24 (1.09) | 2 045 (93.12) | 2 069 |
| dMMR | 115 (5.24) | 12 (0.55) | 127 |
| Total | 139 | 2 057 | 2 196 |
Tab 5
MMR protein expression by IHC of inconsistent microsatellite status
| MMR | MLH1 | MSH2 | MSH6 | PMS2 | n (%) | MMR_ status | MSI_ status |
|---|---|---|---|---|---|---|---|
| Experssion | （+） | （+） | （+） | （+） | 24 (66.67) | pMMR | MSI-H |
| （-） | （+） | （+） | （-） | 6 (16.67) | dMMR | MSS | |
| （+） | （+） | （+） | （-） | 3 (8.33) | dMMR | MSS | |
| （+） | （-） | （-） | （+） | 2 (5.56) | dMMR | MSS | |
| （+） | （+） | （-） | （+） | 1 (2.78) | dMMR | MSS |
Tab 6
Germline mutations in MMR genes of inconsistent microsatellite status by NGS
| Case(n) | Germline mutations | MMR status | MSI status | Gene | Type of variation | Type of causation |
|---|---|---|---|---|---|---|
| 19 | No | pMMR | MSI-H | - | - | - |
| 1 | Yes | pMMR | MSI-H | PMS2 | Stop | Pathogenic |
| 1 | Yes | pMMR | MSI-H | MSH6 | Frame shift insertion | Pathogenic |
| 1 | Yes | pMMR | MSI-H | MSH6 | Frame shift insertion | Likely |
| 1 | Yes | pMMR | MSI-H | MLH1 | Frame shift missing | Pathogenic |
| 1 | Yes | pMMR | MSI-H | PMS2 | Frame shift insertion | Likely |
Tab 7
Clinical characteristics of inconsistent microsatellite status in CRC [n (%)/M(Q1-Q3)]
| Clinical Characteristics | Total (n=2 196) | Consistent （n=2 160） | Inconsistent （n=36） | χ2 value | P value |
|---|---|---|---|---|---|
| Gender | |||||
| Male | 1 313 (59.79) | 1 293 (59.86) | 20 (55.56) | 0.273 0 | 0.601 3 |
| Female | 883 (40.21) | 867 (40.14) | 16 (44.44) | ||
| Age | |||||
| mAge（range） | 61 (20.93) | 63 (20-93) | 63 (29-80) | ||
| ≤60 | 1 075 (48.95) | 1 061 (49.12) | 14 (38.89) | 1.483 3 | 0.223 2 |
| >60 | 1 121 (51.05) | 1 099 (50.88) | 22 (61.11) | ||
| Primary site | |||||
| Left | 1 625 (74.00) | 1 608 (74.44) | 17 (47.22) | 13.637 9 | <0.01 |
| Right | 571 (26.00) | 552 (25.56) | 19 (52.78) | ||
| AJCC | |||||
| Ⅰ-Ⅲ | 1 645 (74.91) | 1 616 (74.81) | 29 (80.56) | 0.620 9 | 0.430 7 |
| Ⅳ | 551 (25.09) | 544 (25.19) | 7 (19.44) | ||
| Differentiation | |||||
| Well | 39 (1.78) | 37 (1.71) | 2 (5.56) | 3.680 3 | 0.158 8 |
| Medium | 1 476 (67.21) | 1 455 (67.36) | 21 (58.33) | ||
| Low | 681 (31.01) | 668 (30.93) | 13 (36.11) |
| [1] | SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. |
| [2] | SIEGEL R L, MILLER K D, WAGLE N S, et al. Cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73(1):17-48. |
| [3] | ZHANG Y, CHEN Z, LI J. The current status of treatment for colorectal cancer in China: a systematic review[J]. Medicine (Baltimore), 2017, 96(40):e8242. |
| [4] | LOUGHREY M B, MCGRATH J, COLEMAN H G, et al. Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series[J]. Histopathology, 2021, 78(3):401-413. |
| [5] |
LATHAM A, SRINIVASAN P, KEMEL Y, et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer[J]. J Clin Oncol, 2019, 37(4): 286-295.
doi: 10.1200/JCO.18.00283 pmid: 30376427 |
| [6] |
YAMAMOTO H, IMAI K. Microsatellite instability: an update[J]. Arch Toxicol, 2015, 89(6):899-921.
doi: 10.1007/s00204-015-1474-0 pmid: 25701956 |
| [7] | CHUNG J, MARUVKA Y E, SUDHAMAN S, et al. DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells[J]. Cancer Discov, 2021, 11(5):1176-1191. |
| [8] | YE M, RU G, YUAN H, et al. Concordance between microsatellite instability and mismatch repair protein expression in colorectal cancer and their clinicopathological characteristics: a retrospective analysis of 502 cases[J]. Front Oncol, 2023,13:1178772. |
| [9] |
CHEN J, YAN Q, SUN J, et al. Microsatellite status detection of colorectal cancer: evaluation of inconsistency between PCR and IHC[J]. J Cancer, 2023, 14(7):1132-1140.
doi: 10.7150/jca.81675 pmid: 37215453 |
| [10] | MIDDHA S, ZHANG L, NAFA K, et al. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data[J]. JCO Precis Oncol, 2017,2017:PO.17.00084. |
| [11] |
NIU B, YE K, ZHANG Q, et al. MSIsensor: microsatellite instability detection using paired tumor-normal sequence data[J]. Bioinformatics, 2014, 30(7):1015-1016.
doi: 10.1093/bioinformatics/btt755 pmid: 24371154 |
| [12] |
LE D T, DURHAM J N, SMITH K N, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349):409-413.
doi: 10.1126/science.aan6733 pmid: 28596308 |
| [13] | DIAO Z, HAN Y, CHEN Y, et al. The clinical utility of microsatellite instability in colorectal cancer[J]. Crit Rev Oncol Hematol, 2021,157:103171. |
| [14] | MARABELLE A, LE D T, ASCIERTO P A, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase Ⅱ KEYNOTE-158 study[J]. J Clin Oncol, 2020, 38(1):1-10. |
| [15] | KAWAKAMI H, ZAANAN A, SINICROPE F A. Microsatellite instability testing and its role in the management of colorectal cancer[J]. Curr Treat Options Oncol, 2015, 16(7):30. |
| [16] | LAU D K, BURGE M, ROY A, et al. Update on optimal treatment for metastatic colorectal cancer from the AGITG expert meeting: ESMO congress 2019[J]. Expert Rev Anticancer Ther, 2020, 20(4):251-270. |
| [17] |
MARCUS L, LEMERY S J, KEEGAN P, et al. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors[J]. Clin Cancer Res, 2019, 25(13):3753-3758.
doi: 10.1158/1078-0432.CCR-18-4070 pmid: 30787022 |
| [18] |
SARGENT D J, MARSONI S, MONGES G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer[J]. J Clin Oncol, 2010, 28(20):3219-3226.
doi: 10.1200/JCO.2009.27.1825 pmid: 20498393 |
| [19] |
COHEN R, HAIN E, BUHARD O, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status[J]. JAMA Oncol, 2019, 5(4):551-555.
doi: 10.1001/jamaoncol.2018.4942 pmid: 30452494 |
| [20] |
YOSHINO T, PENTHEROUDAKIS G, MISHIMA S, et al. JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions[J]. Ann Oncol, 2020, 31(7):861-872.
doi: S0923-7534(20)36386-9 pmid: 32272210 |
| [21] |
DEDEURWAERDERE F, CLAES K B, VAN DORPE J, et al. Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer[J]. Sci Rep, 2021, 11(1):12880.
doi: 10.1038/s41598-021-91974-x pmid: 34145315 |
| [22] |
ADAM R, SPIER I, ZHAO B, et al. Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis[J]. Am J Hum Genet, 2016, 99(2):337-351.
doi: 10.1016/j.ajhg.2016.06.015 pmid: 27476653 |
| [23] | EVRARD C, TACHON G, RANDRIAN V, et al. Microsatellite instability: diagnosis, heterogeneity, discordance, and clinical impact in colorectal cancer[J]. Cancers (Basel), 2019, 11(10):1567. |
| [24] | LI G M. Mechanisms and functions of DNA mismatch repair[J]. Cell Res, 2008, 18(1):85-98. |
| [25] | BAI H, WANG R, CHENG W, et al. Evaluation of concordance between deficient mismatch repair and microsatellite instability testing and their association with clinicopathological features in colorectal cancer[J]. Cancer Manag Res, 2020,12:2863-2873. |
| [26] |
CHEAH P L, LI J, LOOI L M, et al. Screening for microsatellite instability in colorectal carcinoma: practical utility of immunohistochemistry and PCR with fragment analysis in a diagnostic histopathology setting[J]. Malays J Pathol, 2019, 41(2):91-100.
pmid: 31427545 |
| [27] | LUCHINI C, BIBEAU F, LIGTENBERG M J L, et al. ESMO recommendations on microsatellite instability tes-ting for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach[J]. Ann Oncol, 2019, 30(8):1232-1243. |
| [28] |
SALAHSHOR S, KOELBLE K, RUBIO C, et al. Microsatellite instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer[J]. Lab Invest, 2001, 81(4):535-541.
doi: 10.1038/labinvest.3780262 pmid: 11304573 |
| [29] | WANG C, KUANG W, ZENG J, et al. A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer[J]. PeerJ, 2023,11:e15920. |
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