Low prevalence of biliary tract cancer with defective mismatch repair genes in a Japanese hospital‑based population

Ando,Yasuhisa; Kumamoto,Kensuke; Matsukawa,Hiroyuki; Ishikawa,Ryou; Suto,Hironobu; Oshima,Minoru; Kamada,Hideki; Morishita,Asahiro; Kobara,Hideki; Matsunaga,Toru; Haba,Reiji; Masaki,Tsutomu; Suzuki,Yasuyuki; Okano,Keiichi

doi:10.3892/ol.2021.13122

Low prevalence of biliary tract cancer with defective mismatch repair genes in a Japanese hospital‑based population

Authors:
- Yasuhisa Ando
- Kensuke Kumamoto
- Hiroyuki Matsukawa
- Ryou Ishikawa
- Hironobu Suto
- Minoru Oshima
- Hideki Kamada
- Asahiro Morishita
- Hideki Kobara
- Toru Matsunaga
- Reiji Haba
- Tsutomu Masaki
- Yasuyuki Suzuki
- Keiichi Okano
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Affiliations: Department of Gastroenterological Surgery, Kagawa University, Miki, Kagawa 761‑0793, Japan, Department of Diagnostic Pathology, Kagawa University, Miki, Kagawa 761‑0793, Japan, Department of Gastroenterology and Neurology, Kagawa University, Miki, Kagawa 761‑0793, Japan
Published online on: November 4, 2021 https://doi.org/10.3892/ol.2021.13122
Article Number: 4
Copyright: © Ando et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Recent studies have reported that immune checkpoint inhibitors are effective against various defective mismatch repair (dMMR)/microsatellite instability‑high (MSI‑H) cancers. A limited number of reports are available on the frequency of dMMR/MSI‑H carcinoma in biliary tract cancer (BTC), describing its clinicopathological characteristics and prognosis. The latter carcinoma is also associated with Lynch syndrome (LS). The present study was performed to investigate the frequency of patients with dMMR/MSI‑H in BTC and the clinical characteristics of BTC with dMMR/MSI‑H in a single institution in Japan. A total of 116 patients with BTC who underwent curative surgical resection at Kagawa University Hospital between January 2008 and December 2017 were included. The protein expression levels of the mismatch repair (MMR) genes [mutL homolog 1 (MLH1), mismatch repair endonuclease PMS2 (PMS2), MutS homolog (MSH)2 and MSH6] were assessed by immunohistochemistry (IHC) using formalin‑fixed paraffin‑embedded tissue specimens. Subsequently, MSI testing was performed on patients who exhibited loss of MMR protein expression. Loss of expression of one or more proteins was detected in five cases (4.3%). Loss of MLH1/PMS2 expression was observed in one case of intrahepatic cholangiocarcinoma, whereas loss of PMS2 expression was noted in one case of perihilar cholangiocarcinoma. Loss of MSH2/MSH6 and MSH6 expression was noted in two cases of distal cholangiocarcinoma and loss of PMS2 expression in one case of ampullary carcinoma. Out of the five patients, two demonstrated MSI‑H. Microsatellite stability was observed in two cases and for one case, no data were available. Two MSI‑H cases were patients with loss of expression of MLH1/PMS2 and MSH2/MSH6. None of the five patients exhibited a past medical history or family history of suspected LS. The frequency of dMMR in BTC was ~5%, which was similar to that reported by similar studies performed in other countries. In the present study, IHC appeared to be more useful than MSI testing for detecting MMR abnormalities with regards to the detection rate. Furthermore, there may only be a limited number of patients with BTCs who are likely to benefit from the therapeutic effects of treatment with immune checkpoint inhibitors.

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1	Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M, Karlic R, Polak P, Kim J, Hatanaka Y, Maejima K, et al: Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J Hepatol. 68:959–969. 2018. View Article : Google Scholar : PubMed/NCBI
2	Peltomäki P: Update on Lynch syndrome genomics. Fam Cancer. 15:385–393. 2016. View Article : Google Scholar : PubMed/NCBI
3	Pal T, Permuth-Wey J and Sellers TA: A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer. 113:733–742. 2008. View Article : Google Scholar : PubMed/NCBI
4	Agaram NP, Shia J, Tang LH and Klimstra DS: DNA mismatch repair deficiency in ampullary carcinoma: A morphologic and immunohistochemical study of 54 cases. Am J Clin Pathol. 133:772–780. 2010. View Article : Google Scholar : PubMed/NCBI
5	Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen HZ, Reeser JW, Yu L and Roychowdhury S: Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 2017:1–15. 2017. View Article : Google Scholar : PubMed/NCBI
6	Isa T, Tomita S, Nakachi A, Miyazato H, Shimoji H, Kusano T, Muto Y and Furukawa M: Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology. 49:604–608. 2002.PubMed/NCBI
7	Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 357:409–413. 2017. View Article : Google Scholar : PubMed/NCBI
8	Liu D, Momoi H, Li L, Ishikawa Y and Fukumoto M: Microsatellite instability in thorotrast-induced human intrahepatic cholangiocarcinoma. Int J Cancer. 102:366–371. 2002. View Article : Google Scholar : PubMed/NCBI
9	Momoi H, Itoh T, Nozaki Y, Arima Y, Okabe H, Satoh S, Toda Y, Sakai E, Nakagawara K, Flemming P, et al: Microsatellite instability and alternative genetic pathway in intrahepatic cholangiocarcinoma. J Hepatol. 35:235–244. 2001. View Article : Google Scholar : PubMed/NCBI
10	Park S, Kim SW, Kim SH, Darwish NS and Kim WH: Lack of microsatellite instability in neoplasms of ampulla of Vater. Pathol Int. 53:667–670. 2003. View Article : Google Scholar : PubMed/NCBI
11	Rashid A, Ueki T, Gao YT, Houlihan PS, Wallace C, Wang BS, Shen MC, Deng J and Hsing AW: K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: A population-based study in China. Clin Cancer Res. 8:3156–3163. 2002.PubMed/NCBI
12	Ruemmele P, Dietmaier W, Terracciano L, Tornillo L, Bataille F, Kaiser A, Wuensch PH, Heinmoeller E, Homayounfar K, Luettges J, et al: Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions. Am J Surg Pathol. 33:691–704. 2009. View Article : Google Scholar : PubMed/NCBI
13	Salem ME, Puccini A, Grothey A, Raghavan D, Goldberg RM, Xiu J, Korn WM, Weinberg BA, Hwang JJ, Shields AF, et al: Landscape of Tumor Mutation Load, Mismatch Repair Deficiency, and PD-L1 Expression in a Large Patient Cohort of Gastrointestinal Cancers. Mol Cancer Res. 16:805–812. 2018. View Article : Google Scholar : PubMed/NCBI
14	Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F and Capella C: Prognostic factors for ampullary adenocarcinomas: Tumor stage, tumor histology, tumor location, immunohistochemistry and microsatellite instability. Virchows Arch. 451:649–657. 2007. View Article : Google Scholar : PubMed/NCBI
15	Silva VW, Askan G, Daniel TD, Lowery M, Klimstra DS, Abou-Alfa GK and Shia J: Biliary carcinomas: Pathology and the role of DNA mismatch repair deficiency. Chin Clin Oncol. 5:622016. View Article : Google Scholar : PubMed/NCBI
16	Suto T, Habano W, Sugai T, Uesugi N, Kanno S, Saito K and Nakamura S: Infrequent microsatellite instability in biliary tract cancer. J Surg Oncol. 76:121–126. 2001. View Article : Google Scholar : PubMed/NCBI
17	Ueno M, Chung HC, Nagrial A, Marabelle A, Kelley RK, Xu L, Mahoney J, Pruitt SK and Oh DY: Pembrolizumab for advanced biliary adenocarcinoma: Results from the multicohort, phase II KEYNOTE-158 study. Ann Oncol. 29 (Suppl 8):viii2102018. View Article : Google Scholar
18	Winkelmann R, Schneider M, Hartmann S, Schnitzbauer AA, Zeuzem S, Peveling-Oberhag J, Hansmann ML and Walter D: Microsatellite Instability Occurs Rarely in Patients with Cholangiocarcinoma: A Retrospective Study from a German Tertiary Care Hospital. Int J Mol Sci. 19:14212018. View Article : Google Scholar : PubMed/NCBI
19	Anderson C and Kim R: Adjuvant therapy for resected extrahepatic cholangiocarcinoma: A review of the literature and future directions. Cancer Treat Rev. 35:322–327. 2009. View Article : Google Scholar : PubMed/NCBI
20	Brandi G, Farioli A, Astolfi A, Biasco G and Tavolari S: Genetic heterogeneity in cholangiocarcinoma: A major challenge for targeted therapies. Oncotarget. 6:14744–14753. 2015. View Article : Google Scholar : PubMed/NCBI
21	DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ and Schulick RD: Cholangiocarcinoma: Thirty-one-year experience with 564 patients at a single institution. Ann Surg. 245:755–762. 2007. View Article : Google Scholar : PubMed/NCBI
22	Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, et al ABC-02 Trial Investigators, : Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 362:1273–1281. 2010. View Article : Google Scholar : PubMed/NCBI
23	Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, 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 Clin Oncol. 38:1–10. 2020. View Article : Google Scholar : PubMed/NCBI
24	Zayac A and Almhanna K: Hepatobiliary cancers and immunotherapy: Where are we now and where are we heading? Transl Gastroenterol Hepatol. 5:82020. View Article : Google Scholar : PubMed/NCBI
25	Czink E, Kloor M, Goeppert B, Fröhling S, Uhrig S, Weber TF, Meinel J, Sutter C, Weiss KH, Schirmacher P, et al: Successful immune checkpoint blockade in a patient with advanced stage microsatellite-unstable biliary tract cancer. Cold Spring Harb Mol Case Stud. 3:a0019742017. View Article : Google Scholar : PubMed/NCBI
26	Naganuma A, Sakuda T, Murakami T, Aihara K, Watanuki Y, Suzuki Y, Shibasaki E, Masuda T, Uehara S, Yasuoka H, et al: Microsatellite Instability-high Intrahepatic Cholangiocarcinoma with Portal Vein Tumor Thrombosis Successfully Treated with Pembrolizumab. Intern Med. 59:2261–2267. 2020. View Article : Google Scholar : PubMed/NCBI
27	Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, Walsh-Vockley C, Petersen GM, Walsh MD, Leggett BA, et al: Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 20:1043–1048. 2002. View Article : Google Scholar : PubMed/NCBI
28	Mills AM and Longacre TA: Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening. Surg Pathol Clin. 9:201–214. 2016. View Article : Google Scholar : PubMed/NCBI
29	Chaves P, Cruz C, Lage P, Claro I, Cravo M, Leitão CN and Soares J: Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype. J Pathol. 191:355–360. 2000. View Article : Google Scholar : PubMed/NCBI
30	Shia J, Tang LH, Vakiani E, Guillem JG, Stadler ZK, Soslow RA, Katabi N, Weiser MR, Paty PB, Temple LK, et al: Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: A 2-antibody panel may be as predictive as a 4-antibody panel. Am J Surg Pathol. 33:1639–1645. 2009. View Article : Google Scholar : PubMed/NCBI
31	Brierley JD, Gospodarowicz MK and Wittekind C: TNM Classification of Malignant Tumours, 8th Edition. Wiley-Blackwell; 2016
32	Bando H, Okamoto W, Fukui T, Yamanaka T, Akagi K and Yoshino T: Utility of the quasi-monomorphic variation range in unresectable metastatic colorectal cancer patients. Cancer Sci. 109:3411–3415. 2018. View Article : Google Scholar : PubMed/NCBI
33	Akagi K, Oki E, Taniguchi H, Nakatani K, Aoki D, Kuwata T and Yoshino T: The real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer Sci. 112:1105–1113. 2021. View Article : Google Scholar : PubMed/NCBI
34	Moy AP, Shahid M, Ferrone CR, Borger DR, Zhu AX, Ting D and Deshpande V: Microsatellite instability in gallbladder carcinoma. Virchows Arch. 466:393–402. 2015. View Article : Google Scholar : PubMed/NCBI
35	Yoshida T, Sugai T, Habano W, Nakamura S, Uesugi N, Funato O and Saito K: Microsatellite instability in gallbladder carcinoma: Two independent genetic pathways of gallbladder carcinogenesis. J Gastroenterol. 35:768–774. 2000. View Article : Google Scholar : PubMed/NCBI
36	Yanagisawa N, Mikami T, Yamashita K and Okayasu I: Microsatellite instability in chronic cholecystitis is indicative of an early stage in gallbladder carcinogenesis. Am J Clin Pathol. 120:413–417. 2003. View Article : Google Scholar : PubMed/NCBI
37	Nagahashi M, Ajioka Y, Lang I, Szentirmay Z, Kasler M, Nakadaira H, Yokoyama N, Watanabe G, Nishikura K, Wakai T, et al: Genetic changes of p53, K-ras, and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary. World J Gastroenterol. 14:70–75. 2008. View Article : Google Scholar : PubMed/NCBI
38	Shia J: Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn. 10:293–300. 2008. View Article : Google Scholar : PubMed/NCBI
39	Shia J, Ellis NA and Klimstra DS: The utility of immunohistochemical detection of DNA mismatch repair gene proteins. Virchows Arch. 445:431–441. 2004. View Article : Google Scholar : PubMed/NCBI
40	Shia J, Klimstra DS, Nafa K, Offit K, Guillem JG, Markowitz AJ, Gerald WL and Ellis NA: Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol. 29:96–104. 2005. View Article : Google Scholar : PubMed/NCBI
41	Hendriks YM, Jagmohan-Changur S, van der Klift HM, Morreau H, van Puijenbroek M, Tops C, van Os T, Wagner A, Ausems MG, Gomez E, et al: Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology. 130:312–322. 2006. View Article : Google Scholar : PubMed/NCBI
42	Palomaki GE, McClain MR, Melillo S, Hampel HL and Thibodeau SN: EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 11:42–65. 2009. View Article : Google Scholar : PubMed/NCBI
43	Kakar S, Burgart LJ, Thibodeau SN, Rabe KG, Petersen GM, Goldberg RM and Lindor NM: Frequency of loss of hMLH1 expression in colorectal carcinoma increases with advancing age. Cancer. 97:1421–1427. 2003. View Article : Google Scholar : PubMed/NCBI
44	Tajima Y, Eguchi H, Chika N, Nagai T, Dechamethakun S, Kumamoto K, Tachikawa T, Akagi K, Tamaru JI, Seki H, et al: Prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancer in a Japanese hospital-based population. Jpn J Clin Oncol. 48:728–735. 2018. View Article : Google Scholar : PubMed/NCBI
45	Loilome W, Kadsanit S, Muisook K, Yongvanit P, Namwat N, Techasen A, Puapairoj A, Khuntikeo N and Phonjit P: Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma. Oncol Lett. 13:639–646. 2017. View Article : Google Scholar : PubMed/NCBI
46	Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, et al: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 96:261–268. 2004. View Article : Google Scholar : PubMed/NCBI
47	Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, et al: Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 26:5783–5788. 2008. View Article : Google Scholar : PubMed/NCBI
48	Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, et al: Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 35:1086–1095. 2017. View Article : Google Scholar : PubMed/NCBI
49	Valle JW: Advances in the treatment of metastatic or unresectable biliary tract cancer. Ann Oncol. 21 (Suppl 7):vii345–vii348. 2010. View Article : Google Scholar : PubMed/NCBI
50	Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, Kim JS and Thomas CR Jr: Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol. 29:4627–4632. 2011. View Article : Google Scholar : PubMed/NCBI
51	Wang Y, Li J, Xia Y, Gong R, Wang K, Yan Z, Wan X, Liu G, Wu D, Shi L, et al: Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J Clin Oncol. 31:1188–1195. 2013. View Article : Google Scholar : PubMed/NCBI
52	Homet Moreno B and Ribas A: Anti-programmed cell death protein-1/ligand-1 therapy in different cancers. Br J Cancer. 112:1421–1427. 2015. View Article : Google Scholar : PubMed/NCBI
53	Dudley JC, Lin MT, Le DT and Eshleman JR: Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res. 22:813–820. 2016. View Article : Google Scholar : PubMed/NCBI
54	Le DT, Uram JN, Wang H, Kemberling H, Eyring A, Bartlett B, Goldberg RM, Crocenzi TS, Fisher GA, Lee JJ, et al: PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers. J Clin Oncol. 34 (Suppl 4):195. 2016. View Article : Google Scholar