Nat Genet. 2014 Aug;46(8):844-9. doi: 10.1038/ng.3016. Epub 2014 Jun 29.

A Specific Missense Mutation in GTF2I Occurs at High Frequency in Thymic Epithelial

Tumors

Iacopo Petrini 1, Paul S Meltzer 2, In-Kyu Kim 3, Marco Lucchi 4, Kang-Seo Park 3, Gabriella
Fontanini 5, James Gao 1, Paolo A Zucali 6, Fiorella Calabrese 7, Adolfo Favaretto 8, Federico Rea
9, Jaime Rodriguez-Canales 10, Robert L Walker 2, Marbin Pineda 2, Yuelin J Zhu 2, Christopher
Lau 2, Keith J Killian 2, Sven Bilke 2, Donna Voeller 1, Sivanesan Dakshanamurthy 3, Yisong Wang
11, Giuseppe Giaccone 11

Abstract
We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a
missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A
thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation
in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where
recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation
correlated with better survival. GTF2I β and δ isoforms were expressed in TETs, and both mutant
isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher
number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we
identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and
PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of
these tumors and also facilitate development of a molecular classification and assessment of
prognosis and treatment strategies.

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Cell Death Differ. 2020 Feb 7. doi: 10.1038/s41418-020-0502-7. Online ahead of print.

Mutant GTF2I Induces Cell Transformation and Metabolic Alterations in Thymic

Epithelial Cells

In-Kyu Kim 1, Guanhua Rao 2, Xiaoliang Zhao 2, Ruzong Fan 2, Maria Laura Avantaggiati 2, Yisong
Wang 2 3, Yu-Wen Zhang 2, Giuseppe Giaccone 4

Abstract
The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported
the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that
GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the
transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i
L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and
survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression
of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism.
Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under
metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I
mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial
cells.

-------------------------

Lung Cancer. 2017 Aug;110:48-52. doi: 10.1016/j.lungcan.2017.05.020. Epub 2017 May 29.

GTF2I Mutation Frequently Occurs in More Indolent Thymic Epithelial Tumors and
Predicts Better Prognosis

Yanfen Feng 1, Yiyan Lei 2, Xiaoyan Wu 3, Yuhua Huang 4, Huilan Rao 5, Yu Zhang 6, Fang Wang 7

Abstract
Objectives: A missense mutation in GTF2I was previously identified in thymic epithelioid tumor
(TET). However, the clinicopathological relevance of GTF2I mutation has not been illustrated. We
studied the prognostic importance of GTF2I mutation as well as its relation to histological
subtypes in a large number of TETs.

Methods: TET samples from 296 patients with clinical and follow-up data were collected, and
histological subtypes were classified. Analysis of the GTF2I (chromosome 7 c.74146970T>A)
mutation was undertaken by using quantitative real time polymerase chain reaction (qPCR) and
direct sequencing. The association of GTF2I mutation with clinicopathological features as well as
prognosis was analyzed.

Results: One hundred twenty-four out of 296 (41.9%) patients harbored the GTF2I mutation
(chromosome 7 c.74146970T>A). GTF2I mutation was observed in 20 (87.0%) cases of type A
thymoma, 70 (78.7%) of type AB thymoma, and the frequency decreased with the degree of
histological subtype aggressiveness, with the lowest rate in thymic carcinoma (7.7%). The
difference of GTF2I mutation distribution in histological subtypes was statistically significant
(p<0.001). The GTF2I mutation was found more frequently in patients with early Masaoka stage
(I-II, n=112, 90.3%) than in those with advanced stage (III-IV) disease (n=12, 9.6%, p<0.001).
However, only histological subtype significantly predicted the presence of the GTF2I mutation in
patients with TETs. The presence of the GTF2I mutation correlated with better prognosis (90.0%
compared to 72.0% 5-year survival, and 86% compared to 56% 10-year survival, respectively; log-
rank p=0.001). Moreover, it was an independent prognostic factor [hazard ratio (HR), 0.35; 95%
confidential interval (CI), 0.15-0.81; p=0.014)].

Conclusions: The frequency of the GTF2I mutation is higher in more indolent TETs, and correlates
with better prognosis. Further studies are required to elucidate the role of the GTF2I mutation in
TETs and its clinical application.

Keywords: Epithelioid tumor; GTF2I; Mutation; Thymus.

------------------

J Thorac Dis. 2017 Sep;9(9):E808-E814. doi: 10.21037/jtd.2017.07.95.

AB Thymoma With Atypical Type A Component With Delayed Multiple Lung and
Brain Metastases

Wieslawa Grajkowska 1 2, Ewa Matyja 2, Jacek Kunicki 3, Sylwia Szymanska 1, Alexander Marx 4,
Cleo-Aron Weis 4, Renata Langfort 5, Malgorzata Szolkowska 5

Abstract
An atypical type A thymoma is a newly added entity to the last World Health Organization (WHO)
histological classification [2015] of uncertain prognosis. The conventional type A and AB
thymomas are usually locally aggressive neoplasms that rarely metastasize with distant
metastases to the central nervous system (CNS) occurring extremely exceptionally. We present a
history of a woman with a mediastinal tumor originally considered to be a Masaoka-Koga stage II
"mixed thymoma with well-differentiated thymic carcinoma component" according to the historic
Müller-Hermelink nomenclature. By applying the criteria of the new WHO classification the
tumor should be reclassified as an AB thymoma with an atypical A component. The patient
developed metastases to the lung and brain 10 and 15 years after the original diagnosis,
respectively. All metastases morphologically corresponded to an atypical A component of primary
thymoma. Molecular study revealed GTF2I mutations in the primary and one of the metastatic
tumors. To our knowledge, this is the first description of a GTF2I mutation in AB thymoma with
atypical A component and its metastases. The presented case highlights the necessity of an
accurate microscopic search for atypical areas in A or AB thymomas because of their potentially
negative impact on prognosis.

Keywords: GTF2I mutation; Thymoma; atypical type AB thymoma; brain metastases; lung
metastases.

-----------------

Cancer Cell. 2018 Feb 12;33(2):244-258.e10. doi: 10.1016/j.ccell.2018.01.003.

The Integrated Genomic Landscape of Thymic Epithelial Tumors

Milan Radovich 1, Curtis R Pickering 2, Ina Felau 3, Gavin Ha 4, Hailei Zhang 4, Heejoon Jo 5,
Katherine A Hoadley 5, Pavana Anur 6, Jiexin Zhang 2, Mike McLellan 7, Reanne Bowlby 8,
Thomas Matthew 9, Ludmila Danilova 10, Apurva M Hegde 2, Jaegil Kim 4, Mark D M Leiserson
11, Geetika Sethi 12, Charles Lu 7, Michael Ryan 2, Xiaoping Su 2, Andrew D Cherniack 4, Gordon
Robertson 8, Rehan Akbani 2, Paul Spellman 6, John N Weinstein 2, D Neil Hayes 5, Ben Raphael
11, Tara Lichtenberg 13, Kristen Leraas 13, Jean Claude Zenklusen 3, Cancer Genome Atlas
Network; Junya Fujimoto 2, Cristovam Scapulatempo-Neto 14, Andre L Moreira 15, David Hwang
16, James Huang 17, Mirella Marino 18, Robert Korst 19, Giuseppe Giaccone 20, Yesim Gokmen-
Polar 1, Sunil Badve 1, Arun Rajan 3, Philipp Ströbel 21, Nicolas Girard 22, Ming S Tsao 23,
Alexander Marx 24, Anne S Tsao 25, Patrick J Loehrer 26

Abstract
Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma
is the most predominant, characterized by a unique association with autoimmune diseases,
followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-
platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by
genomic hallmarks and an association with survival and World Health Organization histological
subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated
oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe
enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between
thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral
overexpression of muscle autoantigens, and increased aneuploidy.

Keywords: TCGA; autoimmunity; genomics; myasthenia gravis; proteomics; thymic carcinoma;

thymic epithelial tumors; thymoma; transcriptomics.

Dear Prof. Cheung and Dr. Wang,

Followings are what I have read from the literatures I searched

recently:

1. Current status of published studies:

There are totally three independent cohort studies and one case
report on GTF2I mutation in thymic tumors. They show a concordant
result: a specific, recurrent single missense mutation of GTF2I
(chromosome 7 c.74146970T>A, all mutated cases have the this same
mutation) mainly occurs in type A, AB thymoma. The mutated cases have
better prognosis compared to the non-mutated (although this mutation of
GTF2I can cause cell proliferation, the GTF2I non-mutated cases harbor other
more oncogenic mutations to become more malignant).

2. Research methods already used in those studies:

whole exome sequencing (NGS); Sanger sequencing and/or deep sequencing

of the GTF2I locus; mRNA of GTF2I sequencing; western blot;
immunohistochemistry; cell culture of NIH-3T3 cells  (an immortalized
fibroblast cell line) transfected by lentivirus
Methods used by the Chinese cohort (Guangzhou): only qRT-PCR and direct
sequencing on the chromosome 7 c.74146970 locus of GTF2I gene

3. Antibodies used in one of the studies:

anti-TFII-I (4562, Cell Signaling, 1:1,000) for western blot; anti-TFII-I (clone
3E2, EMD Millipore, 1:100) for IHC; the later one is off-sale on official website
The mutated protein (protein name TFII-I) has a different amino acid
(L424H). But the antibodies they used didn't target on that locus, as well as
the currently commercial antibodies.

4. Current IHC study of TFII-I in thymic tumor:

Only one study; mutated cases were nuclear positive, while non-mutated
cases were negative.

5. Research on cytoplasmic and nuclear expression of TFII-I

Using NIH-3T3 cell line as study object by immunofluorescence. Different

isoforms of TFII-I have different subcellular distribution and
function. No related studies on thymic tumor (as well as other tumor). No
isoform-specific antibody commercially available.

6. Current published GTF2I studies on other tumors:

Angioimmunoblastic T-cell lymphoma (Various missense mutations of GTF2I
in different cases, account for 6% of all cases)
Breast cancer (decreased GTF2I mRNA level in cancer cells)
Liver cancer (SUMOylation of TFII-I or tyrosine phosphorylation of TFII-I
enhanced by CD147)
Acute promyelocytic leukemia (GTF2I-RARA t(7;17) (q26;q21) fusion)
Acute lymphoblastic leukemia (GTF2I–PDGFRB fusion)
Glioma (GATSL2-GTF2I fusion)
Pilocytic astrocytoma (GTF2I-BRAF fusion)
Soft tissue angiofibroma (GTF2I-NCOA2 fusion)

Please inform me if you have any questions and I can explain them on the
weekly video meeting. Thank you.

Regards, 

Jiajun Su