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Endocrine
Published in: Endocrine 3/2022

02-04-2022 | Thyroid Cancer | Original Article

Correlation of mismatch repair deficiency with clinicopathological features and programmed death-ligand 1 expression in thyroid carcinoma

Authors: Pei-Pei Qiao, Kai-Sai Tian, Li-Tao Han, Ben Ma, Cen-Kai Shen, Run-Yu Zhao, Yi Zhang, Wen-Jun Wei, Xiao-Ping Chen

Published in: Endocrine | Issue 3/2022

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Abstract

Background

Mutations in DNA mismatch repair (MMR) genes associated with thyroid carcinoma (TC) have rarely been reported, especially in East Asian populations.

Methods

We examined tumor tissue from a cohort of 241 patients diagnosed with TC between 2008 and 2020. MMR proteins were detected using tissue microarray-based immunohistochemistry in order to identify MMR-protein-deficient (MMR-D) and MMR-protein-intact (MMR-I) tumors. We retrospectively summarized the clinicopathologic characteristics of patients with MMR-D TC, measured the expression of PD-L1, and recorded overall survival (OS) and other clinical outcomes.

Results

In our cohort, there were 18 (7.5%) MMR-D (MLH1, MSH2, MSH6, and PMS2) patients, including 12 with papillary TC (PTC) (6.7%), 2 with poorly differentiated TC (PDTC) (4.7%), and 4 with anaplastic TC (ATC) (22.2%). Half of them (9/18) showed a specific deletion in MSH6, and 6 of them also carried variants in the MSH6 and PMS2 gene. Survival was significantly better in patients with MMR-D ATC than in those with MMR-I tumors (p = 0.033). Four of the 18 MMR-D patients (22%) were found to be PD-L1 positive. Their OS was much shorter than that of PD-L1-negative patients.

Conclusions

MMR-D and PD-L1 positivity appear to be associated with clinicopathological characteristics and prognosis in TC. The results indicate that MMR status may have important prognostic significance in TC. Therefore, immune checkpoint inhibitors that target the PD-1/PD-L1 pathway may be a treatment option for TCs.
Literature
1.
2.
3.
S.N. Rao, M. Zafereo, R. Dadu, N.L. Busaidy, K. Hess et al. Patterns of treatment failure in anaplastic. Thyroid Carcinoma Thyroid 27, 672–681 (2017)PubMed
4.
5.
M.J. Overman, R. McDermott, J.L. Leach, S. Lonardi, H.J. Lenz et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017)PubMedPubMedCentralCrossRef
6.
C. Luchini, F. Bibeau, M.J.L. Ligtenberg, N. Singh, A. Nottegar et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann. Oncol. 30, 1232–1243 (2019)PubMedCrossRef
7.
8.
A. Latham, P. Srinivasan, Y. Kemel, J. Shia, C. Bandlamudi et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J. Clin. Oncol. 37, 286–295 (2019)PubMedCrossRef
9.
H. Hampel, W.L. Frankel, E. Martin, M. Arnold, K. Khanduja et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N. Engl. J. Med. 352, 1851–1860 (2005)PubMedCrossRef
10.
H. Hampel, W.L. Frankel, E. Martin, M. Arnold, K. Khanduja et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J. Clin. Oncol. 26, 5783–5788 (2008)PubMedPubMedCentralCrossRef
11.
H. Kawakami, A. Zaanan, F.A. Sinicrope, Microsatellite instability testing and its role in the management of colorectal cancer. Curr. Treat. Options Oncol. 16, 30 (2015)PubMedPubMedCentralCrossRef
12.
K.S. Wong, J.H. Lorch, E.K. Alexander, M.A. Nehs, J.A. Nowak et al. Clinicopathologic features of mismatch repair-deficient anaplastic. Thyroid Carcinomas Thyroid 29, 666–673 (2019)PubMed
13.
B. Evren, S. Yilmaz, N. Karadag, A.C. Sertkaya, O. Topaloglu et al. DNA repair proteins may differentiate papillary thyroid cancer from chronic lymphocytic thyroiditis and nodular colloidal goiter. Sci. Rep. 11, 9932 (2021)PubMedPubMedCentralCrossRef
14.
S. Fujita, K. Masago, Alteration of DNA mismatch repair capacity underlying the co-occurrence of non-small-cell lung cancer and nonmedullary thyroid cancer. Sci. Rep. 11, 3597 (2021)PubMedPubMedCentralCrossRef
15.
M. Javid, T. Sasanakietkul, N.G. Nicolson, C.E. Gibson, G.G. Callender et al. DNA mismatch repair deficiency promotes genomic instability in a subset of papillary thyroid cancers. World J. Surg. 42, 358–366 (2018)PubMedCrossRef
16.
C.Y. Liu, C.S. Huang, C.C. Huang, W.C. Ku, H.Y. Shih et al., Co-occurrence of differentiated thyroid cancer and second primary malignancy: correlation with expression profiles of mismatch repair protein and cell cycle regulators. Cancers. 13, 5486 (2021)
17.
J.S. Maul, N.R. Warner, S.K. Kuwada, R.W. Burt, L.A. Cannon-Albright, Extracolonic cancers associated with hereditary nonpolyposis colorectal cancer in the Utah population database. Am. J. Gastroenterol. 101, 1591–1596 (2006)PubMedCrossRef
18.
E. Mitmaker, C. Alvarado, L.R. Begin, M. Trifiro, Microsatellite instability in benign and malignant thyroid neoplasms. J. Surg. Res. 150, 40–48 (2008)PubMedCrossRef
19.
M. Onda, I. Nakamura, S. Suzuki, S. Takenoshita, C.H. Brogren et al. Microsatellite instability in thyroid cancer: hot spots, clinicopathological implications, and prognostic significance. Clin. Cancer Res. 7, 3444–3449 (2001)PubMed
20.
V. Prasad, V. Kaestner, S. Mailankody, Cancer drugs approved based on biomarkers and not tumor Type-FDA approval of pembrolizumab for mismatch repair-deficient solid cancers. JAMA Oncol. 4, 157–158 (2018)PubMedCrossRef
21.
A. Kythreotou, A. Siddique, F.A. Mauri, M. Bower, D.J. Pinato, Pd-L1. J. Clin. Pathol. 71, 189–194 (2018)PubMedCrossRef
22.
L.A. Diaz Jr., D.T. Le, PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med 373, 1979 (2015)PubMedCrossRef
23.
X. Shi, P.C. Yu, B.W. Lei, C.W. Li, Y. Zhang et al. Association between programmed death-ligand 1 expression and clinicopathological characteristics, structural recurrence, and biochemical recurrence/persistent disease in medullary. Thyroid Carcinoma Thyroid 29, 1269–1278 (2019)PubMed
24.
J. Capdevila, L.J. Wirth, T. Ernst, S. Ponce Aix, C.C. Lin et al. PD-1 blockade in anaplastic thyroid carcinoma. J. Clin. Oncol. 38, 2620–2627 (2020)PubMedPubMedCentralCrossRef
25.
26.
K. Kulangara, N. Zhang, E. Corigliano, L. Guerrero, S. Waldroup et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch. Pathol. Lab. Med. 143, 330–337 (2019)PubMedCrossRef
27.
28.
R. Doghri, Y. Houcine, N. Boujelbene, M. Driss, L. Charfi et al. Mismatch repair deficiency in endometrial cancer: immunohistochemistry staining and clinical implications. Appl. Immunohistochem. Mol. Morphol. 27, 678–682 (2019)PubMedCrossRef
29.
N.B. Schneider, T. Pastor, A.E. Paula, M.I. Achatz, A.R.D. Santos et al. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer Med. 7, 2078–2088 (2018)PubMedPubMedCentralCrossRef
30.
M.E. Roberts, S.A. Jackson, L.R. Susswein, N. Zeinomar, X. Ma et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med. 20, 1167–1174 (2018)PubMedPubMedCentralCrossRef
31.
I. Landa, T. Ibrahimpasic, L. Boucai, R. Sinha, J.A. Knauf et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Investig. 126, 1052–1066 (2016)PubMedPubMedCentralCrossRef
32.
R.P. Graham, S.E. Kerr, M.L. Butz, S.N. Thibodeau, K.C. Halling et al. Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am. J. Surg. Pathol. 39, 1370–1376 (2015)PubMedCrossRef
33.
A. Latham, J. Shia, Z. Patel, D.L. Reidy-Lagunes, N.H. Segal et al. Characterization and Clinical Outcomes of DNA Mismatch Repair-deficient Small Bowel Adenocarcinoma. Clin. Cancer Res. 27, 1429–1437 (2021)PubMedCrossRef
34.
K. Sugano, T. Nakajima, S. Sekine, H. Taniguchi, S. Saito et al. Germline PMS2 mutation screened by mismatch repair protein immunohistochemistry of colorectal cancer in Japan. Cancer Sci. 107, 1677–1686 (2016)PubMedPubMedCentralCrossRef
35.
C.A. Durno, P.M. Sherman, M. Aronson, D. Malkin, C. Hawkins et al. Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome. Eur. J. Cancer 51, 977–983 (2015)PubMedCrossRef
36.
C. Evrard, G. Tachon, V. Randrian, L. Karayan-Tapon, D. Tougeron. microsatellite instability: diagnosis, heterogeneity, discordance, and clinical impact in colorectal cancer. Cancers 11, (2019).
37.
B. Roncari, M. Pedroni, S. Maffei, C. Di Gregorio, G. Ponti et al. Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC. Clin. Genet. 72, 230–237 (2007)PubMedCrossRef
38.
A.J. McCarthy, J.M. Capo-Chichi, T. Spence, S. Grenier, T. Stockley et al. Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation. J. Pathol. Clin. Res. 5, 115–129 (2019)PubMedCrossRef
39.
M.L. Rocha, K.W. Schmid, P. Czapiewski, The prevalence of DNA microsatellite instability in anaplastic thyroid carcinoma - systematic review and discussion of current therapeutic options. Contemp. Oncol. 25, 213–223 (2021)
40.
J.C. Santos, A.U. Bastos, J.M. Cerutti, M.L. Ribeiro, Correlation of MLH1 and MGMT expression and promoter methylation with genomic instability in patients with thyroid carcinoma. BMC Cancer 13, 79 (2013)PubMedPubMedCentralCrossRef
41.
R. Bonneville, M.A. Krook, E.A. Kautto, J. Miya, M.R. Wing et al., Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017, PO.17.00073 (2017).
42.
A.M. Mills, S. Liou, J.M. Ford, J.S. Berek, R.K. Pai et al. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. Am. J. Surg. Pathol. 38, 1501–1509 (2014)PubMedPubMedCentralCrossRef
43.
E. Stelloo, A.M.L. Jansen, E.M. Osse, R.A. Nout, C.L. Creutzberg et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann. Oncol. 28, 96–102 (2017)PubMedCrossRef
44.
M.K. McConechy, A. Talhouk, H.H. Li-Chang, S. Leung, D.G. Huntsman et al. Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. Gynecol. Oncol. 137, 306–310 (2015)PubMedCrossRef
45.
J. Taieb, Q. Shi, L. Pederson, S. Alberts, N. Wolmark et al. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies. Ann. Oncol. 30, 1466–1471 (2019)PubMedPubMedCentralCrossRef
46.
C. Guastadisegni, M. Colafranceschi, L. Ottini, E. Dogliotti, Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur. J. Cancer 46, 2788–2798 (2010)PubMedCrossRef
47.
M. Konishi, R. Kikuchi-Yanoshita, K. Tanaka, M. Muraoka, A. Onda et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 111, 307–317 (1996)PubMedCrossRef
48.
S. Markowitz, J. Wang, L. Myeroff, R. Parsons, L. Sun et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995)PubMedCrossRef
49.
H. Kim, J. Jen, B. Vogelstein, S.R. Hamilton, Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol. 145, 148–156 (1994)PubMedPubMedCentral
50.
M. Dominguez-Valentin, J.R. Sampson, T.T. Seppala, S.W. Ten Broeke, J.P. Plazzer et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 22, 15–25 (2020)PubMedCrossRef
51.
L.S. Santos, B.C. Gomes, H.N. Bastos, O.M. Gil, A.P. Azevedo et al., Thyroid cancer: the quest for genetic susceptibility involving DNA repair genes. Genes 10, 586 (2019).
52.
S. Ahn, T.H. Kim, S.W. Kim, C.S. Ki, H.W. Jang et al. Comprehensive screening for PD-L1 expression in thyroid cancer. Endocr. Relat. Cancer 24, 97–106 (2017)PubMedCrossRef
53.
S. Chowdhury, J. Veyhl, F. Jessa, O. Polyakova, A. Alenzi et al. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget 7, 32318–32328 (2016)PubMedPubMedCentralCrossRef
54.
J.J. Bastman, H.S. Serracino, Y. Zhu, M.R. Koenig, V. Mateescu et al. Tumor-Infiltrating T cells and the PD-1 checkpoint pathway in advanced differentiated and anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 101, 2863–2873 (2016)PubMedPubMedCentralCrossRef
55.
T.E. Angell, M.G. Lechner, J.K. Jang, A.J. Correa, J.S. LoPresti et al. BRAF V600E in papillary thyroid carcinoma is associated with increased programmed death ligand 1 expression and suppressive immune cell infiltration. Thyroid 24, 1385–1393 (2014)PubMedPubMedCentralCrossRef
56.
L.L. Cunha, M.A. Marcello, E.C. Morari, S. Nonogaki, F.F. Conte et al. Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation. Endocr. Relat. Cancer 20, 103–110 (2013)PubMedCrossRef
57.
F. Loupakis, G. Maddalena, I. Depetris, S. Murgioni, F. Bergamo et al. Treatment with checkpoint inhibitors in a metastatic colorectal cancer patient with molecular and immunohistochemical heterogeneity in MSI/dMMR status. J. Immunother. Cancer 7, 297 (2019)PubMedPubMedCentralCrossRef
58.
T. Yoshino, G. Pentheroudakis, S. Mishima, M.J. Overman, K.H. Yeh 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. Ann. Oncol. 31, 861–872 (2020)PubMedCrossRef
59.
M.J. Overman, S. Lonardi, K.Y.M. Wong, H.J. Lenz, F. Gelsomino et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018)PubMedCrossRef
Metadata
Title
Correlation of mismatch repair deficiency with clinicopathological features and programmed death-ligand 1 expression in thyroid carcinoma
Authors
Pei-Pei Qiao
Kai-Sai Tian
Li-Tao Han
Ben Ma
Cen-Kai Shen
Run-Yu Zhao
Yi Zhang
Wen-Jun Wei
Xiao-Ping Chen
Publication date
02-04-2022
Publisher
Springer US
Published in
Endocrine / Issue 3/2022
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-022-03031-w

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WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

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