Top

Published in:

01-12-2021 | Anemia | Research

Whole-exome sequencing reveals the etiology of the rare primary hepatic mucoepidermoid carcinoma

Authors: Ping Hou, Xiaoyan Su, Wei Cao, Liping Xu, Rongguiyi Zhang, Zhihao Huang, Jiakun Wang, Lixiang Li, Linquan Wu, Wenjun Liao

Published in: Diagnostic Pathology | Issue 1/2021

Abstract

Background

Primary hepatic mucoepidermoid carcinoma (HMEC) is extremely rare and the molecular etiology is still unknown. The CRTC1-MAML2 fusion gene was previously detected in a primary HMEC, which is often associated with MEC of salivary gland in the literature.

Methods

A 64-year-old male was diagnosed with HMEC based on malignant squamous cells and mucus-secreting cells in immunohistochemical examination. Fluorescence in situ hybridization (FISH) was used to detect the CRTC1-MAML2 fusion gene in HMEC. Whole-exome sequencing and Sanger sequencing were used to reveal the molecular characteristics of HMEC and analysis was performed with public data. Pedigree investigation was performed to identify susceptibility genes.

Results

Hematoxylin–eosin staining and immunohistochemistry revealed that the tumor cells were composed of malignant epidermoid malignant cells and mucous cells, indicating a diagnosis of HMEC. The CRTC1-MAML2 fusion gene was not detected in the primary HMEC, and somatic mutations in GNAS, KMT2C and ELF3 genes were identified by sequencing. Analyses of public data revealed somatic GNAS alterations in 2.1% hepatobiliary tumors and relation with parasite infection. Heterozygous germline mutations of FANCA, FANCI, FANCJ/BRIP1 and FAN1 genes were also identified. Pedigree investigation verified that mutation of Fanconi’s anemia susceptibility genes were present in the pedigree.

Conclusions

Here we provide the first evidence of the molecular etiology of a rare HMEC associated with germline Fanconi’s anemia gene mutations and somatic GNAS R201H mutation.

Available only for authorised users

Nallacheruvu Y, Gaur K, Sakhuja P, Agarwal AK, Srivastava S. Mucoepidermoid carcinoma of the gallbladder: a case-based study of an extremely rare tumor highlighting the role of immunohistochemical profiling. Int J Surg Pathol. 2019;27(4):418–22. https://doi.org/10.1177/1066896918821436 PubMed PMID: 30587051.CrossRefPubMed

Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet. 2003;33(2):208–13. https://doi.org/10.1038/ng1083 PubMed PMID: 12539049.CrossRefPubMed

Lennerz JK, Perry A, Mills JC, Huettner PC, Pfeifer JD. Mucoepidermoid carcinoma of the cervix: another tumor with the t(11;19)-associated CRTC1-MAML2 gene fusion. Am J Surg Pathol. 2009;33(6):835–43. https://doi.org/10.1097/PAS.0b013e318190cf5b PubMed PMID: 19092631.CrossRefPubMed

Achcar RDOD, Nikiforova MN, Dacic S, Nicholson AG, Yousem SA. Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma. Hum Pathol. 2009;40(6):854–60. https://doi.org/10.1016/j.humpath.2008.11.007.CrossRef

Saeki K, Ohishi Y, Matsuda R, Mochidome N, Miyasaka Y, Yamamoto H, et al. “Pancreatic mucoepidermoid carcinoma” is not a pancreatic counterpart of CRTC1/3-MAML2 fusion gene-related mucoepidermoid carcinoma of the salivary gland, and may more appropriately be termed pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features. Am J Surg Pathol. 2018;42(11):1419–28. https://doi.org/10.1097/PAS.0000000000001135 PubMed PMID: 30138216.CrossRefPubMed

Watanabe J, Kai K, Tanikawa K, Hiraki M, Mizukami N, Aishima S, et al. Primary mucoepidermoid carcinoma of the liver with CRTC1-MAML2 fusion: a case report. Diagn Pathol. 2019;14(1):84. https://doi.org/10.1186/s13000-019-0863-8 PubMed PMID: 31351495.CrossRefPubMedPubMedCentral

Moul AE, Bejarano PA, Casillas J, Levi JU, Garcia-Buitrago MT. Mucoepidermoid carcinoma of the Intrapancreatic common bile duct: immunohistochemical profile, prognosis, and review of the literature. Case Rep Pathol. 2013;2013:1–5. https://doi.org/10.1155/2013/192458.CrossRef

Deeg HJ, Socie G, Schoch G, Henry-Amar M, Witherspoon RP, Devergie A, et al. Malignancies after marrow transplantation for aplastic anemia and fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood. 1996;87(1):386–92. PubMed PMID: 8547667. https://doi.org/10.1182/blood.V87.1.386.386.CrossRefPubMed

Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25(14):1754–60. https://doi.org/10.1093/bioinformatics/btp324 PubMed PMID: 19451168.CrossRefPubMedPubMedCentral

10.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078–9. https://doi.org/10.1093/bioinformatics/btp352 PubMed PMID: 19505943.CrossRefPubMedPubMedCentral

11.

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164. https://doi.org/10.1093/nar/gkq603 PubMed PMID: 20601685.CrossRefPubMedPubMedCentral

12.

Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65. https://doi.org/10.1038/nature11632 PubMed PMID: 23128226.CrossRefPubMed

13.

Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11. https://doi.org/10.1093/nar/29.1.308 PubMed PMID: 11125122.CrossRefPubMedPubMedCentral

14.

Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006. https://doi.org/10.1101/gr.229102 PubMed PMID: 12045153.CrossRefPubMedPubMedCentral

15.

Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213–9. https://doi.org/10.1038/nbt.2514 PubMed PMID: 23396013.CrossRefPubMedPubMedCentral

16.

Saunders CT, Wong WS, Swamy S, Becq J, Murray LJ, Cheetham RK. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics. 2012;28(14):1811–7. https://doi.org/10.1093/bioinformatics/bts271 PubMed PMID: 22581179.CrossRefPubMed

17.

Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;Chapter 7:t7–20. https://doi.org/10.1002/0471142905.hg0720s76 PubMed PMID: 23315928.CrossRef

18.

Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812–4. https://doi.org/10.1093/nar/gkg509 PubMed PMID: 12824425.CrossRefPubMedPubMedCentral

19.

Miosge LA, Field MA, Sontani Y, Cho V, Johnson S, Palkova A, et al. Comparison of predicted and actual consequences of missense mutations. Proc Natl Acad Sci U S A. 2015;112(37):E5189–98. https://doi.org/10.1073/pnas.1511585112 PubMed PMID: 26269570.CrossRefPubMedPubMedCentral

20.

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):l1. https://doi.org/10.1126/scisignal.2004088 PubMed PMID: 23550210.CrossRef

21.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data: figure 1. Cancer Discov. 2012;2(5):401–4. https://doi.org/10.1158/2159-8290.CD-12-0095.CrossRefPubMed

22.

Kang H, Tan M, Bishop JA, Jones S, Sausen M, Ha PK, et al. Whole-exome sequencing of salivary gland Mucoepidermoid carcinoma. Clin Cancer Res. 2017;23(1):283–8. https://doi.org/10.1158/1078-0432.CCR-16-0720.CrossRefPubMed

23.

Zhu AX, D'Andrea AD, Sahani DV, Hasserjian RP. Case 13-2006: a 50-year-old man with a painful bone mass and lesions in the liver. N Engl J Med. 2006;354(17):1828–37. https://doi.org/10.1056/NEJMcpc069004.CrossRefPubMed

24.

Linares M, Pastor E, Gomez A, Grau E. Hepatocellular carcinoma and squamous cell carcinoma in a patient with Fanconi’s anemia. Ann Hematol. 1991;63(1):54–5. https://doi.org/10.1007/BF01714963 PubMed PMID: 1652289.CrossRefPubMed

25.

Nalepa G, Clapp DW. Fanconi anaemia and cancer: an intricate relationship. Nat Rev Cancer. 2018;18(3):168–85. https://doi.org/10.1038/nrc.2017.116.CrossRefPubMed

26.

Alter BP, Greene MH, Velazquez I, Rosenberg PS. Cancer in Fanconi anemia. Blood. 2003;101(5):2072. https://doi.org/10.1182/blood-2002-11-3597 PubMed PMID: 12584146.CrossRefPubMed

27.

Kang H, Park YN, Kim SE, Sohn KR, Yoo NC, Park JY, et al. Double primary mucoepidermoid carcinoma and hepatocellular carcinoma of the liver--a case report. Hepatogastroenterology. 2003;50(49):238–41 PubMed PMID: 12630031.PubMed

28.

Nishiyama M, Mizukami Y, Kume M, Ogawa A, Jinno A, Kisaka Y, et al. Mucoepidermoid carcinoma of the intrahepatic bile duct with metastasis to the cranial skin. Nihon Shokakibyo Gakkai Zasshi. 2012;109(11):1953–9 PubMed PMID: 23132041.CrossRefPubMed

29.

Hayashi I, Tomoda H, Tanimoto M, Furusawa M, Katsuda Y, Shirai S, et al. Mucoepidermoid carcinoma arising from a preexisting cyst of the liver. J Surg Oncol. 1987;36(2):122–5. https://doi.org/10.1002/jso.2930360210 PubMed PMID: 3309470.CrossRefPubMed

30.

Nepal M, Che R, Zhang J, Ma C, Fei P. Fanconi anemia signaling and cancer. Trends Cancer. 2017;3(12):840–56. https://doi.org/10.1016/j.trecan.2017.10.005.CrossRefPubMedPubMedCentral

31.

Wang AT, Smogorzewska A. SnapShot: Fanconi anemia and associated proteins. Cell. 2015;160(1–2):354–354.e1. https://doi.org/10.1016/j.cell.2014.12.031.CrossRefPubMed

32.

Wang SS, Bratti MC, Rodriguez AC, Herrero R, Burk RD, Porras C, et al. Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer. J Infect Dis. 2009;199(1):20–30. https://doi.org/10.1086/595563 PubMed PMID: 19012493.CrossRefPubMed

33.

Cecener G, Egeli U, Tunca B, Erturk E, Ak S, Gokgoz S, et al. BRCA1/2 germline mutations and their clinical importance in Turkish breast cancer patients. Cancer Investig. 2014;32(8):375–87. https://doi.org/10.3109/07357907.2014.919302 PubMed PMID: 24884828.CrossRef

34.

Lachaud C, Moreno A, Marchesi F, Toth R, Blow JJ, Rouse J. Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability. Science. 2016;351(6275):846–9. https://doi.org/10.1126/science.aad5634.CrossRefPubMedPubMedCentral

35.

Smith AL, Alirezaie N, Connor A, Chan-Seng-Yue M, Grant R, Selander I, et al. Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer. Cancer Lett. 2016;370(2):302–12. https://doi.org/10.1016/j.canlet.2015.10.030.CrossRefPubMed

36.

Segui N, Mina LB, Lazaro C, Sanz-Pamplona R, Pons T, Navarro M, et al. Germline mutations in FAN1 cause hereditary colorectal cancer by impairing DNA repair. Gastroenterology. 2015;149(3):563–6. https://doi.org/10.1053/j.gastro.2015.05.056 PubMed PMID: 26052075.CrossRefPubMed

37.

O'Hayre M, Vázquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S, et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat Rev Cancer. 2013;13(6):412–24. https://doi.org/10.1038/nrc3521.CrossRefPubMedPubMedCentral

38.

Nault JC, Fabre M, Couchy G, Pilati C, Jeannot E, Tran Van Nhieu J, et al. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. J Hepatol. 2012;56(1):184–91. https://doi.org/10.1016/j.jhep.2011.07.018.CrossRefPubMed

39.

Di Palma S, Andreola S, Audisio RA, Doci R, Lombardi L. Primary mucoepidermoid carcinoma of the liver. A case report. Tumori. 1992;78(1):65–8. PubMed PMID: 1609465. https://doi.org/10.1177/030089169207800117.CrossRefPubMed

40.

Katsuda S, Nakanishi I, Kajikawa K, Takabatake S. Mucoepidermoid carcinoma of the liver. Acta Pathol Jpn. 1984;34(1):153–7. https://doi.org/10.1111/j.1440-1827.1984.tb02194.x PubMed PMID: 6730963.CrossRefPubMed

41.

Patra KC, Kato Y, Mizukami Y, Widholz S, Boukhali M, Revenco I, et al. Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol. 2018;20(7):811–22. https://doi.org/10.1038/s41556-018-0122-3.CrossRefPubMedPubMedCentral

42.

Berger AW, Schwerdel D, Costa IG, Hackert T, Strobel O, Lam S, et al. Detection of hot-spot mutations in circulating cell-free DNA from patients with intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2016;151(2):267–70. https://doi.org/10.1053/j.gastro.2016.04.034.CrossRefPubMed

43.

Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003–10. https://doi.org/10.1038/ng.3375.CrossRefPubMed

44.

Chan-on W, Nairismägi M, Ong CK, Lim WK, Dima S, Pairojkul C, et al. Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers. Nat Genet. 2013;45(12):1474–8. https://doi.org/10.1038/ng.2806.CrossRefPubMed

45.

Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I, Yu W, et al. Exome sequencing of liver fluke–associated cholangiocarcinoma. Nat Genet. 2012;44(6):690–3. https://doi.org/10.1038/ng.2273.CrossRefPubMed

46.

Koo J, Ho J, Wong J, Ong GB. Mucoepidermoid carcinoma of the bile duct. Ann Surg. 1982;196(2):140–8. https://doi.org/10.1097/00000658-198208000-00005 PubMed PMID: 7092364.CrossRefPubMedPubMedCentral

47.

Jee KJ, Persson M, Heikinheimo K, Passador-Santos F, Aro K, Knuutila S, et al. Genomic profiles and CRTC1-MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma. Mod Pathol. 2013;26(2):213–22. https://doi.org/10.1038/modpathol.2012.154.CrossRefPubMed

48.

Yan L, Xie F, Yang C, Yu L, Zheng T, Fu J, et al. The comparison of surgical patients with primary hepatic squamous cell carcinoma or adenosquamous carcinoma and surgical patients with hepatocellular carcinoma. World J Surg Oncol. 2015;13(1):90. https://doi.org/10.1186/s12957-015-0464-2.CrossRefPubMedPubMedCentral

49.

Boeva V, Popova T, Bleakley K, Chiche P, Cappo J, Schleiermacher G, et al. Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data. Bioinformatics. 2012;28(3):423–5. https://doi.org/10.1093/bioinformatics/btr670 PubMed PMID: 22155870.CrossRefPubMed

50.

Farges O, Ferreira N, Dokmak S, Belghiti J, Bedossa P, Paradis V. Changing trends in malignant transformation of hepatocellular adenoma. Gut. 2010;60(1):85–9. https://doi.org/10.1136/gut.2010.222109.CrossRef

51.

Yang CY, Huang WJ, Tsai JH, Cheng A, Chen CC, Hsu HP, et al. Targeted next-generation sequencing identifies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct. Mod Pathol. 2019;32(11):1637–45. https://doi.org/10.1038/s41379-019-0306-9 PubMed PMID: 31231124.CrossRefPubMed

Title: Whole-exome sequencing reveals the etiology of the rare primary hepatic mucoepidermoid carcinoma
Authors: Ping Hou
Xiaoyan Su
Wei Cao
Liping Xu
Rongguiyi Zhang
Zhihao Huang
Jiakun Wang
Lixiang Li
Linquan Wu
Wenjun Liao
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Anemia
Fluorescence in Situ Hybridization
Cholangiocarcinoma
Cholangiocarcinoma
Published in: Diagnostic Pathology / Issue 1/2021
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/s13000-021-01086-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Whole-exome sequencing reveals the etiology of the rare primary hepatic mucoepidermoid carcinoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Sialadenoma papilliferum: clinicopathologic, Immunohistochemical, molecular analyses of new five cases and review of the literature

Needle tract seeding in renal tumor biopsies: experience from a single institution

CpG islands in MyD88 and ASC/PYCARD/TMS1 promoter regions are differentially methylated in head and neck squamous cell carcinoma and primary lung squamous cell carcinoma

Artificial intelligence (AI) in medicine, current applications and future role with special emphasis on its potential and promise in pathology: present and future impact, obstacles including costs and acceptance among pathologists, practical and philosophical considerations. A comprehensive review

MAEL as a diagnostic marker for the early detection of esophageal squamous cell carcinoma

Expressions of TWIST1 and CD105 markers in colorectal cancer patients and their association with metastatic potential and prognosis