Comprehensive analysis of genomic alterations of Chinese hilar cholangiocarcinoma patients.
Biomarker
Cholangiocarcinoma
Disease-free survival
Genomic alteration
Tumor mutational burden
Journal
International journal of clinical oncology
ISSN: 1437-7772
Titre abrégé: Int J Clin Oncol
Pays: Japan
ID NLM: 9616295
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
25
08
2020
accepted:
23
11
2020
pubmed:
3
1
2021
medline:
24
3
2021
entrez:
2
1
2021
Statut:
ppublish
Résumé
Cholangiocarcinoma (CCA) is a rare malignant tumor of the biliary system. The heterogeneity of CCA leads to the lack of effective targeted treatment for CCA subtypes. The molecular characteristic of hilar CCA (hCCA) is still unclear. A total of 63 hCCA patients were enrolled from Shanghai Eastern Hepatobiliary Surgery Hospital. Formalin-fixed, paraffin-embedded tumor tissues, and matched blood were collected and deep sequencing targeting 450 cancer genes were performed. Tumor mutation burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher's exact test. The most commonly mutated genes were TP53 (51.7%), NF1 and KRAS (20%, for both), SMAD4 (16.7%), FAT3 and FRS2 (13.3%, for both), NF1 (11.7%), and KMT2C, MDM2, and ATM (10%, for each) in hCCA. ARID1A, GATA6, and PREX2 mutations commonly occurred in female and KMT2C mutations mainly occurred in patients under 60 years old. Statistical analysis showed the association between ARID1A mutation and tumor stage (P = 0.041) and between NF1 mutation and high TMB (P = 0.0095). Furthermore, ARID1B mutation was identified to associate with the poor prognosis of Chinese hCCA patients (P = 0.004). The mutational characterization of hCCA is different from both extrahepatic CCA and intrahepatic CCA. ARID1B is a potential biomarker for prognosis prediction of Chinese hCCA patients.
Sections du résumé
BACKGROUND
BACKGROUND
Cholangiocarcinoma (CCA) is a rare malignant tumor of the biliary system. The heterogeneity of CCA leads to the lack of effective targeted treatment for CCA subtypes. The molecular characteristic of hilar CCA (hCCA) is still unclear.
METHODS
METHODS
A total of 63 hCCA patients were enrolled from Shanghai Eastern Hepatobiliary Surgery Hospital. Formalin-fixed, paraffin-embedded tumor tissues, and matched blood were collected and deep sequencing targeting 450 cancer genes were performed. Tumor mutation burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher's exact test.
RESULTS
RESULTS
The most commonly mutated genes were TP53 (51.7%), NF1 and KRAS (20%, for both), SMAD4 (16.7%), FAT3 and FRS2 (13.3%, for both), NF1 (11.7%), and KMT2C, MDM2, and ATM (10%, for each) in hCCA. ARID1A, GATA6, and PREX2 mutations commonly occurred in female and KMT2C mutations mainly occurred in patients under 60 years old. Statistical analysis showed the association between ARID1A mutation and tumor stage (P = 0.041) and between NF1 mutation and high TMB (P = 0.0095). Furthermore, ARID1B mutation was identified to associate with the poor prognosis of Chinese hCCA patients (P = 0.004).
CONCLUSION
CONCLUSIONS
The mutational characterization of hCCA is different from both extrahepatic CCA and intrahepatic CCA. ARID1B is a potential biomarker for prognosis prediction of Chinese hCCA patients.
Identifiants
pubmed: 33387086
doi: 10.1007/s10147-020-01846-z
pii: 10.1007/s10147-020-01846-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
717-727Subventions
Organisme : Shanghai Municipal Health Commission Integrative Innovation Project
ID : 2019CXJQ03
Références
Chen P, Li B, Zhu Y et al (2016) Establishment and validation of a prognostic nomogram for patients with resectable perihilar cholangiocarcinoma. Oncotarget 7(24):37319–37330. https://doi.org/10.18632/oncotarget.9104
doi: 10.18632/oncotarget.9104
pubmed: 27144432
pmcid: 5095079
Rizvi S, Gores GJ (2013) Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145(6):1215–1229. https://doi.org/10.1053/j.gastro.2013.10.013
doi: 10.1053/j.gastro.2013.10.013
pubmed: 24140396
Jarnagin WR, Fong Y, DeMatteo RP et al (2001) Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234(4):507–517. https://doi.org/10.1097/00000658-200110000-00010
doi: 10.1097/00000658-200110000-00010
pubmed: 11573044
pmcid: 1422074
Hidalgo E, Asthana S, Nishio H et al (2008) Surgery for hilar cholangiocarcinoma: the Leeds experience. Eur J Surg Oncol 34(7):787–794. https://doi.org/10.1016/j.ejso.2007.10.005
doi: 10.1016/j.ejso.2007.10.005
pubmed: 18036765
Yoo T, Park SJ, Han SS et al (2018) Proximal resection margins: more prognostic than distal resection margins in patients undergoing hilar cholangiocarcinoma resection. Cancer Res Treat 50(4):1106–1113. https://doi.org/10.4143/crt.2017.320
doi: 10.4143/crt.2017.320
pubmed: 29141394
Schacke G (1985) Danger to pregnant women at the work site. Disagreement between employers and trade unions in the USA: sterilization or employment termination. Fortschr der Medizin 103(47–48):52–53
Du J, Zhou XJ (2017) Precise diagnosis and treatment of thymic epithelial tumors based on molecular biomarkers. Crit Rev Oncog 22(5–6):507–514. https://doi.org/10.1615/CritRevOncog.2017020577
doi: 10.1615/CritRevOncog.2017020577
pubmed: 29604928
Hainsworth JD, Meric-Bernstam F, Swanton C et al (2018) Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from mypathway, an open-label, phase IIa multiple basket study. J Clin Oncol 36(6):536–542. https://doi.org/10.1200/jco.2017.75.3780
doi: 10.1200/jco.2017.75.3780
pubmed: 29320312
Miyazaki M, Ohtsuka M, Miyakawa S et al (2015) Classification of biliary tract cancers established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepato-Biliary-Pancreat Sci 22(3):181–196. https://doi.org/10.1002/jhbp.211
doi: 10.1002/jhbp.211
Huggett MT, Passant H, Hurt C et al (2014) Outcome and patterns of care in advanced biliary tract carcinoma (ABC): experience from two tertiary institutions in the United Kingdom. Tumori 100(2):219–224. https://doi.org/10.1700/1491.16421
doi: 10.1700/1491.16421
pubmed: 24852869
Churi CR, Shroff R, Wang Y et al (2014) Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS ONE 9(12):e115383. https://doi.org/10.1371/journal.pone.0115383
doi: 10.1371/journal.pone.0115383
pubmed: 25536104
pmcid: 4275227
Tian W, Hu W, Shi X et al (2020) Comprehensive genomic profile of cholangiocarcinomas in China. Oncol Lett 19(4):3101–3110. https://doi.org/10.3892/ol.2020.11429
doi: 10.3892/ol.2020.11429
pubmed: 32256810
pmcid: 7074170
Nakamura H, Arai Y, Totoki Y et al (2015) Genomic spectra of biliary tract cancer. Nat Genet 47(9):1003–1010. https://doi.org/10.1038/ng.3375
doi: 10.1038/ng.3375
pubmed: 26258846
Waseem D, Tushar P (2017) Intrahepatic, perihilar and distal cholangiocarcinoma: Management and outcomes. Ann Hepatol 16(1):133–139. https://doi.org/10.5604/16652681.1226927
doi: 10.5604/16652681.1226927
pubmed: 28051802
Cao J, Chen L, Li H et al (2019) An accurate and comprehensive clinical sequencing assay for cancer targeted and immunotherapies. Oncologist 24(12):e1294–e1302. https://doi.org/10.1634/theoncologist.2019-0236
doi: 10.1634/theoncologist.2019-0236
pubmed: 31409745
pmcid: 6975945
Bismuth H, Corlette MB (1975) Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstetr 140(2):170–178
Chakravarty D, Gao J, Phillips SM et al (2017) OncoKB: a precision oncology knowledge base. JCO Precis Oncol. https://doi.org/10.1200/po.17.00011
doi: 10.1200/po.17.00011
pubmed: 28890946
pmcid: 5558263
Esnaola NF, Meyer JE, Karachristos A et al (2016) Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer 122(9):1349–1369. https://doi.org/10.1002/cncr.29692
doi: 10.1002/cncr.29692
pubmed: 26799932
Akita M, Fujikura K, Ajiki T et al (2017) Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas. Mod Pathol 30(7):986–997. https://doi.org/10.1038/modpathol.2017.22
doi: 10.1038/modpathol.2017.22
pubmed: 28338651
Xue L, Guo C, Zhang K et al (2019) Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice. Hepatobiliary Surg Nutr 8(6):615–622. https://doi.org/10.21037/hbsn.2019.08.05
doi: 10.21037/hbsn.2019.08.05
pubmed: 31929988
pmcid: 6943002
Lowery MA, Ptashkin R, Jordan E et al (2018) Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res 24(17):4154–4161. https://doi.org/10.1158/1078-0432.ccr-18-0078
doi: 10.1158/1078-0432.ccr-18-0078
pubmed: 29848569
pmcid: 6642361
Abdel-Wahab R, Liu S, Cao J et al (2019) AB045. P-13. genomic heterogeneity between Asian and Western intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr 8:45–45. https://doi.org/10.21037/hbsn.2019.AB045
doi: 10.21037/hbsn.2019.AB045
He X, Pang Z, Zhang X et al (2018) Consistent amplification of FRS2 and MDM2 in low-grade osteosarcoma: a genetic study of 22 cases with clinicopathologic analysis. Am J Surg Pathol 42(9):1143–1155. https://doi.org/10.1097/pas.0000000000001125
doi: 10.1097/pas.0000000000001125
pubmed: 30001240
Ware PL, Snow AN, Gvalani M et al (2014) MDM2 copy numbers in well-differentiated and dedifferentiated liposarcoma: characterizing progression to high-grade tumors. Am J Clin Pathol 141(3):334–341. https://doi.org/10.1309/ajcplyu89xhsnhqo
doi: 10.1309/ajcplyu89xhsnhqo
pubmed: 24515760
Gotoh N (2008) Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci 99(7):1319–1325. https://doi.org/10.1111/j.1349-7006.2008.00840.x
doi: 10.1111/j.1349-7006.2008.00840.x
pubmed: 18452557
Manuvakhova M, Thottassery JV, Hays S et al (2006) Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells. Oncogene 25(44):6003–6014. https://doi.org/10.1038/sj.onc.1209592
doi: 10.1038/sj.onc.1209592
pubmed: 16682955
Zhong X, Xie G, Zhang Z et al (2016) MiR-4653-3p and its target gene FRS2 are prognostic biomarkers for hormone receptor positive breast cancer patients receiving tamoxifen as adjuvant endocrine therapy. Oncotarget 7(38):61166–61182. https://doi.org/10.18632/oncotarget.11278
doi: 10.18632/oncotarget.11278
pubmed: 27533459
pmcid: 5308643
Fujimoto A, Totoki Y, Abe T et al (2012) Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 44(7):760–764. https://doi.org/10.1038/ng.2291
doi: 10.1038/ng.2291
pubmed: 22634756
Zang ZJ, Cutcutache I, Poon SL et al (2012) Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 44(5):570–574. https://doi.org/10.1038/ng.2246
doi: 10.1038/ng.2246
pubmed: 22484628
Li WD, Li QR, Xu SN et al (2013) Exome sequencing identifies an MLL3 gene germ line mutation in a pedigree of colorectal cancer and acute myeloid leukemia. Blood 121(8):1478–1479. https://doi.org/10.1182/blood-2012-12-470559
doi: 10.1182/blood-2012-12-470559
pubmed: 23429989
Chen C, Liu Y, Rappaport RA et al (2014) MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25(5):652–665. https://doi.org/10.1016/j.ccr.2014.03.016
doi: 10.1016/j.ccr.2014.03.016
pubmed: 24794707
pmcid: 4206212
Sato K, Akimoto K (2017) Expression levels of KMT2C and SLC20A1 identified by information-theoretical analysis are powerful prognostic biomarkers in estrogen receptor-positive breast cancer. Clin Breast Cancer 17(3):e135–e142. https://doi.org/10.1016/j.clbc.2016.11.005
doi: 10.1016/j.clbc.2016.11.005
pubmed: 27986439
Wang Y (2019) Association between histone lysine methyltransferase KMT2C mutation and clinicopathological factors in breast cancer. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2019.108997
doi: 10.1016/j.biopha.2019.108997
pubmed: 31919040
Rao RC, Dou Y (2015) Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer 15(6):334–346. https://doi.org/10.1038/nrc3929
doi: 10.1038/nrc3929
pubmed: 25998713
pmcid: 4493861
Hr B, Da S, Frank M (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348(6297):125–132. https://doi.org/10.1038/348125a0
doi: 10.1038/348125a0
Side L, Taylor B, Cayouette M et al (1997) Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med 336(24):1713–1720. https://doi.org/10.1056/nejm199706123362404
doi: 10.1056/nejm199706123362404
pubmed: 9180088
Basu TN, Gutmann DH, Fletcher JA et al (1992) Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356(6371):713–715. https://doi.org/10.1038/356713a0
doi: 10.1038/356713a0
pubmed: 1570015
High TMB predicts immunotherapy benefit (2018). Cancer Discov 8(6):668. https://doi.org/10.1158/2159-8290.cd-nb2018-048
Chalmers ZR, Connelly CF, Fabrizio D et al (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9(1):34. https://doi.org/10.1186/s13073-017-0424-2
doi: 10.1186/s13073-017-0424-2
pubmed: 28420421
pmcid: 5395719
Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856. https://doi.org/10.1158/1535-7163.mct-14-0983
doi: 10.1158/1535-7163.mct-14-0983
pubmed: 25695955
Mou H, Yu L, Liao Q et al (2018) Successful response to the combination of immunotherapy and chemotherapy in cholangiocarcinoma with high tumour mutational burden and PD-L1 expression: a case report. BMC Cancer 18(1):1105. https://doi.org/10.1186/s12885-018-5021-2
doi: 10.1186/s12885-018-5021-2
pubmed: 30419854
pmcid: 6233589
Wang S, Liechty B, Patel S et al (2018) Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors. J Neurooncol 138(1):183–190. https://doi.org/10.1007/s11060-018-2788-6
doi: 10.1007/s11060-018-2788-6
pubmed: 29427150
pmcid: 5930071
Kim T, Yoo J, Wang Z et al (2015) ARID1A Is essential for endometrial function during early pregnancy. PLoS Genet 11(9):e1005537. https://doi.org/10.1371/journal.pgen.1005537
doi: 10.1371/journal.pgen.1005537
pubmed: 26378916
pmcid: 4574948
Yang S, Wang A, Du J et al (2016) Low expression of ARID1A correlates with poor prognosis in intrahepatic cholangiocarcinoma. World J Gastroenterol 22(25):5814–5821. https://doi.org/10.3748/wjg.v22.i25.5814
doi: 10.3748/wjg.v22.i25.5814
pubmed: 27433094
pmcid: 4932216
Zhang L, Jia CW, Lu ZH et al (2016) ARID1A expression of SWI/SNF remodeling complex in pancreatic neuroendocrine tumor. Chin J Pathol 45(8):571–574. https://doi.org/10.3760/cma.j.issn.0529-5807.2016.08.015
doi: 10.3760/cma.j.issn.0529-5807.2016.08.015
Sasaki M, Sato Y, Nakanuma Y (2017) Mutational landscape of combined hepatocellular carcinoma and cholangiocarcinoma, and its clinicopathological significance. Histopathology 70(3):423–434. https://doi.org/10.1111/his.13084
doi: 10.1111/his.13084
pubmed: 27634656
Shen W, Niu N, Lawson B et al (2019) GATA6: a new predictor for prognosis in ovarian cancer. Hum Pathol 86:163–169. https://doi.org/10.1016/j.humpath.2019.01.001
doi: 10.1016/j.humpath.2019.01.001
pubmed: 30633927
Spolverato G, Ejaz A, Kim Y et al (2014) Tumor size predicts vascular invasion and histologic grade among patients undergoing resection of intrahepatic cholangiocarcinoma. J Gastrointest Surg 18(7):1284–1291. https://doi.org/10.1007/s11605-014-2533-1
doi: 10.1007/s11605-014-2533-1
pubmed: 24841438
Guan JL, Zhong WZ, An SJ et al (2013) KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol 20(4):1381–1388. https://doi.org/10.1245/s10434-012-2754-z
doi: 10.1245/s10434-012-2754-z
pubmed: 23208128
Lin G, Zheng XW, Li C et al (2012) KRAS mutation and NF-κB activation indicates tolerance of chemotherapy and poor prognosis in colorectal cancer. Dig Dis Sci 57(9):2325–2333. https://doi.org/10.1007/s10620-012-2172-x
doi: 10.1007/s10620-012-2172-x
pubmed: 22526587
Khursheed M, Kolla J, Kotapalli V et al (2013) ARID1B, a member of the human SWI/SNF chromatin remodeling complex, exhibits tumour-suppressor activities in pancreatic cancer cell lines. Br J Cancer 108(10):2056–2062. https://doi.org/10.1038/bjc.2013.200
doi: 10.1038/bjc.2013.200
pubmed: 23660946
pmcid: 3670478
Wang B, Xie H, Ma C et al (2017) Expression of ARID1B Is associated with poor outcomes and predicts the benefit from adjuvant chemotherapy in bladder urothelial carcinoma. J Cancer 8(17):3490–3497. https://doi.org/10.7150/jca.19109
doi: 10.7150/jca.19109
pubmed: 29151933
pmcid: 5687163
Wang M, Fan W, Ye M et al (2018) Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers. Sci Rep 8(1):8990. https://doi.org/10.1038/s41598-018-25583-6
doi: 10.1038/s41598-018-25583-6
pubmed: 29895933
pmcid: 5997642
Zhao J, Sun Y, Huang Y et al (2017) Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing. Sci Rep 7:40488. https://doi.org/10.1038/srep40488
doi: 10.1038/srep40488
pubmed: 28091594
pmcid: 5238425
Jackson T, Du L, Janesko-Feldman K et al (2015) The nuclear splicing factor RNA binding motif 5 promotes caspase activation in human neuronal cells, and increases after traumatic brain injury in mice. J Cereb Blood Flow Metab 35(4):655–666. https://doi.org/10.1038/jcbfm.2014.242
doi: 10.1038/jcbfm.2014.242
pubmed: 25586139
pmcid: 4420885
Giannakis M, Mu X, Shukla S et al (2016) Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep 15(4):857–865. https://doi.org/10.1016/j.celrep.2016.03.075
doi: 10.1016/j.celrep.2016.03.075
pubmed: 27149842
pmcid: 4850357
Loiselle JJ, Roy JG, Sutherland LC (2017) RBM10 promotes transformation-associated processes in small cell lung cancer and is directly regulated by RBM5. PLoS ONE 12(6):e0180258. https://doi.org/10.1371/journal.pone.0180258
doi: 10.1371/journal.pone.0180258
pubmed: 28662214
pmcid: 5491171
Yin LL, Wen XM, Li M et al (2018) A gene mutation in RNA-binding protein 10 is associated with lung adenocarcinoma progression and poor prognosis. Oncol Lett 16(5):6283–6292. https://doi.org/10.3892/ol.2018.9496
doi: 10.3892/ol.2018.9496
pubmed: 30405763
pmcid: 6202477