Molecular Genetics of Thymic Carcinoma

Abstract

Thymic carcinoma (TC) is a rare cancer with poor survival. Therapeutic regimen and drug clinical efficacy after failure of first‐line chemotherapy have not fully developed yet. Next‐generation sequencing studies were recently performed in patients with TC from Asian and Europe/US cohorts and reported genomic and epigenomic aberrations, including actionable aberrations for developing targeted personalised therapies. Some somatic variants, such as CYLD, TP53, HRAS and RB1, were commonly identified in both Asian and Europe/US cohorts, suggesting their contribution to thymic carcinogenesis. In addition to somatic mutations, epigenomic aberrations and gene rearrangements have been identified in TC. Mutational signature analysis revealed an accumulation of age‐related variants and DNA mismatch repair deficiency derived from TC development. The efforts to find novel actionable targets are continuing and immunotherapy for TC is investigated. Several clinical trials are currently underway to evaluate the therapeutic utility of immunotherapy for TC.

Key Concepts

  • Genomic and epigenomic aberrations in thymic carcinoma have been revealed.
  • Targeted therapy and immunotherapy for thymic carcinoma have been developed.
  • Thymic carcinoma is a rare cancer with poor survival.
  • Efficient therapeutic drugs after failure of the first‐line chemotherapy are required.
  • Genomic and epigenomic aberrations in thymic carcinoma have been revealed.
  • Targeted therapies for thymic carcinoma is being developed.
  • Efficacy of immunotherapy is expected for thymic carcinoma.

Keywords: thymic carcinoma; next‐generation sequencing; targeted therapy; immunotherapy

Figure 1. Genetic aberration profile of ten Japanese patients with thymic carcinoma. Average (a) and each (b) distribution of six categories of nucleotide substitution (C>A, C>G, C>T, T>A, T>C, T>G). Ti: nucleotide transition. Tv: nucleotide transversion.
Figure 2. Distribution of 96 nucleotide substitution spectra based on the neighbouring bases immediately 5′ and 3′ of the mutated base in the ten Japanese patients with thymic carcinoma.
Figure 3. Molecular aberration profile in ten Japanese patients with thymic carcinoma (TC). (a) Genes in the cancer gene census, chromatin remodelling genes (ch) and recurrently mutated genes in TC. Mutations registered in the COSMIC (Catalogue of Somatic Mutations in Cancer) database are marked by dots. (b) Genes with gain of expression. Focal copy number (CN) gains are indicated by upward arrows. (c) Genes with loss of expression. Truncating or splicing site mutation or focal CN losses are indicated by downward arrows. (d) Gene fusion detected in TC.
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References

Alberobello AT, Wang Y, Beerkens FJ, et al. (2016) PI3K as a potential therapeutic target in thymic epithelial tumors. Journal of Thoracic Oncology 11: 1345–1356.

Alexandrov LB, Nik‐Zainal S, Wedge DC, et al. (2013) Signatures of mutational processes in human cancer. Nature 500: 415–421.

Biankin AV, Waddell N, Kassahn KS, et al. (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491: 399–405.

Burns MB, Temiz NA and Harris RS (2013) Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics 45: 977–983.

Buti S, Donini M, Sergio P, et al. (2011) Impressive response with imatinib in a heavily pretreated patient with metastatic c‐KIT mutated thymic carcinoma. Journal of Clinical Oncology 29: e803–e805.

Cancer Genome Atlas Network (2012a) Comprehensive molecular portraits of human breast tumours. Nature 490: 61–70.

Cancer Genome Atlas Network (2012b) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487: 330–337.

Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474: 609–615.

Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489: 519–525.

Cancer Genome Atlas Research Network (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499: 43–49.

Cancer Genome Atlas Research Network (2014a) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511: 543–550.

Cancer Genome Atlas Research Network (2014b) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513: 202–209.

Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497: 67–73.

Conforti F, Zhang X, Rao G, et al. (2017) Therapeutic effects of XPO1 inhibition in thymic epithelial tumors. Cancer Research 77: 5614–5627.

Devarakonda S, Rotolo F, Tsao MS, et al. (2018) Tumor mutation burden as a biomarker in resected non‐small‐cell lung cancer. Journal of Clinical Oncology: JCO2018781963.

Garber K (2018) Blood test may predict cancer immunotherapy benefit. Science 360: 1387.

Garon EB, Rizvi NA, Hui R, et al. (2015) Pembrolizumab for the treatment of non‐small‐cell lung cancer. The New England Journal of Medicine 372: 2018–2028.

Giaccone G, Kim C, Thompson J, et al. (2018) Pembrolizumab in patients with thymic carcinoma: a single‐arm, single‐centre, phase 2 study. The Lancet Oncology 19: 347–355.

Girard N (2012) Chemotherapy and targeted agents for thymic malignancies. Expert Review of Anticancer Therapy 12: 685–695.

Greene MA and Malias MA (2003) Aggressive multimodality treatment of invasive thymic carcinoma. The Journal of Thoracic and Cardiovascular Surgery 125: 434–436.

Herbst RS, Soria JC, Kowanetz M, et al. (2014) Predictive correlates of response to the anti‐PD‐L1 antibody MPDL3280A in cancer patients. Nature 515: 563–567.

Kandoth C, McLellan MD, Vandin F, et al. (2013) Mutational landscape and significance across 12 major cancer types. Nature 502: 333–339.

Katsuya Y, Fujita Y, Horinouchi H, et al. (2015) Immunohistochemical status of PD‐L1 in thymoma and thymic carcinoma. Lung Cancer 88: 154–159.

Kohno T (2018) Implementation of “clinical sequencing” in cancer genome medicine in Japan. Cancer Science 109: 507–512.

Mandal R and Chan TA (2016) Personalized oncology meets immunology: the path toward precision immunotherapy. Cancer Discovery 6: 703–713.

Matsushita H, Vesely MD, Koboldt DC, et al. (2012) Cancer exome analysis reveals a T‐cell‐dependent mechanism of cancer immunoediting. Nature 482: 400–404.

Owen D, Chu B, Lehman AM, et al. (2018) Expression patterns, prognostic value, and intratumoral heterogeneity of PD‐L1 and PD‐1 in thymoma and thymic carcinoma. Journal of Thoracic Oncology 13: 1204–1212.

Petrini I, Meltzer PS, Kim IK, et al. (2014) A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nature Genetics 46: 844–849.

Powles T, Eder JP, Fine GD, et al. (2014) MPDL3280A (anti‐PD‐L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515: 558–562.

Radovich M, Pickering CR, Felau I, et al. (2018) The integrated genomic landscape of thymic epithelial tumors. Cancer Cell 33: 244–258.e10.

Rizvi NA, Hellmann MD, Snyder A, et al. (2015) Cancer immunology. Mutational landscape determines sensitivity to PD‐1 blockade in non‐small cell lung cancer. Science 348: 124–128.

Saito M, Fujiwara Y, Asao T, et al. (2017) The genomic and epigenomic landscape in thymic carcinoma. Carcinogenesis 38: 1084–1091.

Saito M, Momma T and Kono K (2018) Targeted therapy according to next generation sequencing‐based panel sequencing. Fukushima Journal of Medical Science 64: 9–14.

Saito M, Shiraishi K, Kunitoh H, et al. (2016) Gene aberrations for precision medicine against lung adenocarcinoma. Cancer Science 107: 713–720.

Strobel P, Hartmann M, Jakob A, et al. (2004) Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. The New England Journal of Medicine 350: 2625–2626.

Thomas A, Rajan A, Berman A, et al. (2015) Sunitinib in patients with chemotherapy‐refractory thymoma and thymic carcinoma: an open‐label phase 2 trial. The Lancet Oncology 16: 177–186.

Topalian SL, Hodi FS, Brahmer JR, et al. (2012) Safety, activity, and immune correlates of anti‐PD‐1 antibody in cancer. The New England Journal of Medicine 366: 2443–2454.

Totoki Y, Yoshida A, Hosoda F, et al. (2014) Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma. Genome Research 24: 1411–1420.

Wang Y, Thomas A, Lau C, et al. (2014) Mutations of epigenetic regulatory genes are common in thymic carcinomas. Scientific Reports 4: 7336.

Weissferdt A, Wistuba II and Moran CA (2012) Molecular aspects of thymic carcinoma. Lung Cancer 78: 127–132.

Yudong S, Zhaoting M, Xinyue W, et al. (2018) EGFR exon 20 insertion mutation in advanced thymic squamous cell carcinoma: response to apatinib and clinical outcomes. Thorac Cancer 9: 885–891.

Further Reading

Futreal PA, Coin L, Marshall M, et al. (2004) A census of human cancer genes. Nature Reviews. Cancer 4: 177–183.

Hellmann MD, Ciuleanu TE, Pluzanski A, et al. (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. The New England Journal of Medicine 378: 2093–2104.

Miao D, Margolis CA, Vokes NI, et al. (2018) Genomic correlates of response to immune checkpoint blockade in microsatellite‐stable solid tumors. Nature Genetics 50: 1271–1281.

Robles AI and Harris CC (2017) Integration of multiple “OMIC” biomarkers: a precision medicine strategy for lung cancer. Lung Cancer 107: 50–58.

Saito M, Saito K, Shiraishi K, et al. (2018) Identification of candidate responders for anti‐PD‐L1/PD‐1 immunotherapy, Rova‐T therapy, or EZH2 inhibitory therapy in small‐cell lung cancer. Molecular and Clinical Oncology 8: 310–314.

Saito M, Shimada Y, Shiraishi K, et al. (2015) Development of lung adenocarcinomas with exclusive dependence on oncogene fusions. Cancer Research 75: 2264–2271.

Saito M, Shiraishi K, Goto A, et al. (2018) Development of targeted therapy and immunotherapy for treatment of small cell lung cancer. Japanese Journal of Clinical Oncology 48: 603–608.

Saito M, Suzuki H, Kono K, et al. (2018) Treatment of lung adenocarcinoma by molecular‐targeted therapy and immunotherapy. Surgery Today 48: 1–8.

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Saito, Motonobu, Kono, Koji, and Kohno, Takashi(May 2019) Molecular Genetics of Thymic Carcinoma. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028455]