Tumor Genetics and Cytogenetics: Solid Tumors

  • Natasha RekhtmanEmail author
  • Marina K Baine
  • Justin A. Bishop


Recurrent chromosomal translocations have traditionally been associated with leukemias/lymphomas and sarcomas. Translocations cause either formation of chimeric proteins (such as BCR-ABL) or abnormal protein expression (such as overexpression of c-Myc as a result of translocation into Ig promoter sequences in Burkitt lymphoma). In contrast, carcinomas generally have complex karyotypes with no recurrent translocations. Instead, carcinomas typically have activating mutations in proto-oncogenes (e.g., KRAS) or inactivation of tumor suppressor genes (e.g., TP53). In recent years this paradigm has shifted, and an increasing number of carcinomas are being recognized as having recurrent translocations. Notable examples are salivary carcinomas, pediatric renal cell carcinoma, thyroid carcinoma, and some lung adenocarcinomas.


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  1. 1.
    Kao YC, Owosho AA, Sung YS, et al. BCOR-CCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am J Surg Pathol. 2018;42:604–15.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Kao YC, Sung YS, Zhang L, et al. BCOR overexpression is a highly sensitive marker in round cell sarcomas with BCOR genetic abnormalities. Am J Surg Pathol. 2016;40:1670–8.CrossRefGoogle Scholar
  3. 3.
    Le Guellec S, Velasco V, Perot G, et al. ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions. Mod Pathol. 2016;29:1523–31.CrossRefGoogle Scholar
  4. 4.
    Shibuya R, Matsuyama A, Shiba E, et al. CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid haemangioendothelioma. Histopathology. 2015;67:827–35.CrossRefGoogle Scholar
  5. 5.
    Hung YP, Fletcher CD, Hornick JL. Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma. Mod Pathol. 2016;29:370–80.CrossRefGoogle Scholar
  6. 6.
    Yoshida A, Sekine S, Tsuta K, et al. NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma. Am J Surg Pathol. 2012;36:993–9.CrossRefGoogle Scholar
  7. 7.
    Antonescu CR, Suurmeijer AJ, Zhang L, et al. Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol. 2015;39:957–67.CrossRefGoogle Scholar
  8. 8.
    Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest. 2005;85:408–15.CrossRefGoogle Scholar
  9. 9.
    Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol. 2007;31:1813–24.CrossRefGoogle Scholar
  10. 10.
    Brandal P, Panagopoulos I, Bjerkehagen B, et al. t(19;22)(q13;q12) Translocation leading to the novel fusion gene EWSR1-ZNF444 in soft tissue myoepithelial carcinoma. Genes Chromosomes Cancer. 2009;48:1051–6.CrossRefGoogle Scholar
  11. 11.
    Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Invest. 2011;91:1427–33.CrossRefGoogle Scholar
  12. 12.
    Argani P, Aulmann S, Illei PB, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol. 2010;34:1395–406.CrossRefGoogle Scholar
  13. 13.
    Williamson D, Missiaglia E, de Reynies A, et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol. 2010;28:2151–8.CrossRefGoogle Scholar
  14. 14.
    Doyle LA, Wang WL, Dal Cin P, et al. MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am J Surg Pathol. 2012;36:1444–51.CrossRefGoogle Scholar
  15. 15.
    Brill LB 2nd, Kanner WA, Fehr A, et al. Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms. Mod Pathol. 2011;24:1169–76.CrossRefGoogle Scholar
  16. 16.
    Kim J, Geyer FC, Martelotto LG, et al. MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene. J Pathol. 2018;244:143–50.CrossRefGoogle Scholar
  17. 17.
    Fehr A, Kovacs A, Loning T, et al. The MYB-NFIB gene fusion-a novel genetic link between adenoid cystic carcinoma and dermal cylindroma. J Pathol. 2011;224:322–7.CrossRefGoogle Scholar
  18. 18.
    Bishop JA, Yonescu R, Epstein JI, et al. A subset of prostatic basal cell carcinomas harbor the MYB rearrangement of adenoid cystic carcinoma. Hum Pathol. 2015;46:1204–8.CrossRefGoogle Scholar
  19. 19.
    Jo VY, Sholl LM, Krane JF. Distinctive patterns of CTNNB1 (beta-Catenin) alterations in salivary gland basal cell adenoma and basal cell adenocarcinoma. Am J Surg Pathol. 2016;40:1143–50.CrossRefGoogle Scholar
  20. 20.
    Wilson TC, Ma D, Tilak A, et al. Next-generation sequencing in salivary gland basal cell adenocarcinoma and basal cell adenoma. Head Neck Pathol. 2016;10:494–500.CrossRefGoogle Scholar
  21. 21.
    Shah AA, LeGallo RD, van Zante A, et al. EWSR1 genetic rearrangements in salivary gland tumors: a specific and very common feature of hyalinizing clear cell carcinoma. Am J Surg Pathol. 2013;37:571–8.CrossRefGoogle Scholar
  22. 22.
    Antonescu CR, Katabi N, Zhang L, et al. EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland. Genes Chromosomes Cancer. 2011;50:559–70.CrossRefGoogle Scholar
  23. 23.
    Dalin MG, Desrichard A, Katabi N, et al. Comprehensive molecular characterization of salivary duct carcinoma reveals actionable targets and similarity to apocrine breast cancer. Clin Cancer Res. 2016;22:4623–33.CrossRefGoogle Scholar
  24. 24.
    El Hallani S, Udager AM, Bell D, et al. Epithelial-myoepithelial carcinoma: frequent morphologic and molecular evidence of preexisting pleomorphic adenoma, common HRAS mutations in PLAG1-intact and HMGA2-intact cases, and occasional TP53, FBXW7, and SMARCB1 alterations in high-grade cases. Am J Surg Pathol. 2018;42:18–27.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Weinreb I, Bishop JA, Chiosea SI, et al. Recurrent RET gene rearrangements in intraductal carcinomas of salivary gland. Am J Surg Pathol. 2018;42:442–52.CrossRefGoogle Scholar
  26. 26.
    Okabe M, Miyabe S, Nagatsuka H, et al. MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma. Clin Cancer Res. 2006;12:3902–7.CrossRefGoogle Scholar
  27. 27.
    Seethala RR, Chiosea SI. MAML2 status in mucoepidermoid carcinoma can no longer be considered a prognostic marker. Am J Surg Pathol. 2016;40:1151–3.CrossRefGoogle Scholar
  28. 28.
    Bishop JA, Cowan ML, Shum CH, et al. MAML2 rearrangements in variant forms of mucoepidermoid carcinoma: ancillary diagnostic testing for the ciliated and warthin-like variants. Am J Surg Pathol. 2018;42:130–6.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Winnes M, Molne L, Suurkula M, et al. Frequent fusion of the CRTC1 and MAML2 genes in clear cell variants of cutaneous hidradenomas. Genes Chromosomes Cancer. 2007;46:559–63.CrossRefGoogle Scholar
  30. 30.
    Katabi N, Ghossein R, Ho A, et al. Consistent PLAG1 and HMGA2 abnormalities distinguish carcinoma ex-pleomorphic adenoma from its de novo counterparts. Hum Pathol. 2015;46:26–33.CrossRefGoogle Scholar
  31. 31.
    Persson F, Andren Y, Winnes M, et al. High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosomes Cancer. 2009;48:69–82.CrossRefGoogle Scholar
  32. 32.
    Mito JK, Jo VY, Chiosea SI, et al. HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex-pleomorphic adenoma. Histopathology. 2017;71:511–21.CrossRefGoogle Scholar
  33. 33.
    Martins C, Fonseca I, Roque L, et al. PLAG1 gene alterations in salivary gland pleomorphic adenoma and carcinoma ex-pleomorphic adenoma: a combined study using chromosome banding, in situ hybridization and immunocytochemistry. Mod Pathol. 2005;18:1048–55.CrossRefGoogle Scholar
  34. 34.
    Weinreb I, Piscuoglio S, Martelotto LG, et al. Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands. Nat Genet. 2014;46:1166–9.CrossRefGoogle Scholar
  35. 35.
    Weinreb I, Zhang L, Tirunagari LM, et al. Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin. Genes Chromosomes Cancer. 2014;53:845–56.CrossRefGoogle Scholar
  36. 36.
    Clauditz TS, Reiff M, Gravert L, et al. Human epidermal growth factor receptor 2 (HER2) in salivary gland carcinomas. Pathology. 2011;43:459–64.CrossRefGoogle Scholar
  37. 37.
    Chiosea SI, Williams L, Griffith CC, et al. Molecular characterization of apocrine salivary duct carcinoma. Am J Surg Pathol. 2015;39:744–52.CrossRefGoogle Scholar
  38. 38.
    Griffith CC, Seethala RR, Luvison A, et al. PIK3CA mutations and PTEN loss in salivary duct carcinomas. Am J Surg Pathol. 2013;37:1201–7.CrossRefGoogle Scholar
  39. 39.
    Skalova A, Vanecek T, Sima R, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34:599–608.PubMedGoogle Scholar
  40. 40.
    Skalova A, Vanecek T, Martinek P, et al. Molecular profiling of mammary analog secretory carcinoma revealed a subset of tumors harboring a novel ETV6-RET translocation: report of 10 cases. Am J Surg Pathol. 2018;42:234–46.CrossRefGoogle Scholar
  41. 41.
    Brat DJ, Verhaak RG, Aldape KD, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372:2481–98.CrossRefGoogle Scholar
  42. 42.
    Bandopadhayay P, Ramkissoon LA, Jain P, et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet. 2016;48:273–82.CrossRefGoogle Scholar
  43. 43.
    Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:465–72.CrossRefGoogle Scholar
  44. 44.
    Argani P, Lae M, Hutchinson B, et al. Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol. 2005;29:230–40.CrossRefGoogle Scholar
  45. 45.
    Karlsson J, Valind A, Gisselsson D. BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney. Genes Chromosomes Cancer. 2016;55:120–3.CrossRefGoogle Scholar
  46. 46.
    Pugh TJ, Morozova O, Attiyeh EF, et al. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45:279–84.CrossRefGoogle Scholar
  47. 47.
    Nicolai S, Pieraccioli M, Peschiaroli A, et al. Neuroblastoma: oncogenic mechanisms and therapeutic exploitation of necroptosis. Cell Death Dis. 2015;6:e2010.CrossRefGoogle Scholar
  48. 48.
    Woodman SE, Davies MA. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem Pharmacol. 2010;80:568–74.CrossRefGoogle Scholar
  49. 49.
    Haack H, Johnson LA, Fry CJ, et al. Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol. 2009;33:984–91.CrossRefGoogle Scholar
  50. 50.
    Fine SW, Gopalan A, Leversha MA, et al. TMPRSS2-ERG gene fusion is associated with low Gleason scores and not with high-grade morphological features. Mod Pathol. 2010;23:1325–33.CrossRefGoogle Scholar
  51. 51.
    Park K, Tomlins SA, Mudaliar KM, et al. Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia. 2010;12:590–8.CrossRefGoogle Scholar
  52. 52.
    Marino-Enriquez A, Lauria A, Przybyl J, et al. BCOR internal tandem duplication in high-grade uterine sarcomas. Am J Surg Pathol. 2018;42:335–41.CrossRefGoogle Scholar
  53. 53.
    Chiang S, Lee CH, Stewart CJR, et al. BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol. 2017;30:1251–61.CrossRefGoogle Scholar
  54. 54.
    Lewis N, Soslow RA, Delair DF, et al. ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. Mod Pathol. 2018;31:674–84.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Natasha Rekhtman
    • 1
    Email author
  • Marina K Baine
    • 2
  • Justin A. Bishop
    • 3
  1. 1.Department of PathologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Department of PathologyYale New Haven Hospital, Yale School of MedicineNew HavenUSA
  3. 3.Department of PathologyUniversity of Texas Southwestern Medical CenterDallasUSA

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