ONCOLOGY REPORTS 28: 1225-1230, 2012
Abstract. In a screen for thoracic malignancy-associated
markers, thyroid stimulating hormone receptor (TSHR)
was identified as a candidate as it binds to the previously-
characterized lung cancer marker NKX2-1. We screened for
mutations in all coding regions of the TSHR gene in 96 lung
adenocarcinoma samples and their matched adjacent normal
lung samples. We found one patient with a somatic mutation
at codon 458 (exon 10), which is located at the transmembrane
domain where most TSHR mutations have been found in
thyroid-related diseases. This patient had lung adenocarci-
noma with BAC (bronchioloalveolar carcinoma) features in
the setting of a prior medical history significant for carotid
stenosis and severe chronic obstructive pulmonary disease
(COPD). In order to characterize the genetic features of TSHR
in lung cancer, we checked for TSHR expression and copy
number in the 96 lung cancer tissues. TSHR protein expression
was generally overexpressed in multiple thoracic malignancies
(adenocarcinoma, squamous cell carcinoma and malignant
pleural mesothelioma) by immunohistochemistry. Our data
suggest that aberrant TSHR function may contribute to lung
cancer development or a subgroup of lung cancer with specific
Lung cancer is one of the worst prognostic human cancers,
taking more lives than any other human cancer worldwide (1).
Progress in therapy for lung cancer has made recent progress
with the identification of molecular markers such as EGFR and
EML4-ALK (2-4). Gefitinib (Tarceva) targeting EGFR and
Crizotinib (Xalkori) targeting EML4-ALK are leading exam-
ples of molecular targeting in lung cancer therapeutics (2,4).
Patients with EGFR mutations have responded well to Tarceva.
However, many patients later relapse due to a secondary EGFR
mutation (T790M), decreasing the advantage of Tarceva treat-
ment with respect to patient prognosis and survival (5). In 2007,
a new fusion protein, EML4-ALK, was identified in a Japanese
lung cancer patient without EGFR or K-ras mutations (3). The
incidence of this fusion protein is greater in Asian patients
without EGFR or K-ras mutations (6). Encouragingly, patients
with EML4-ALK showed a dramatic response to an ALK
inhibitor (7) and in 2011, the FDA approved Crizotinib for the
treatment of non-small-cell lung cancer (NSCLC) in patients
with EML4-ALK fusion and aberrant ALK expression. Overall
mutation frequencies of EGFR and EML4-ALK are ~25% and
1-7% (3,6), respectively, which suggests that >65% of lung
cancer patients lack specific molecular targets for treatment.
Identification of new targets either for diagnosis or therapy is
important in the effort to reduce mortality by lung cancer.
NKX2-1 (TTF1 or TITF1 or thyroid transcription factor-1)
was originally identified in thyroid and lung (8). Many efforts
have been made to identify characteristics of NKX2-1 not only
in thyroid but also in other organs, including the lung. NKX2-1
was first thought to act as a lung oncogene (9,10), but later
study suggested that it may act as a tumor suppressor in lung
adenocarcinoma (11). Notwithstanding the clear contribution
of NKX2-1 to lung development and homeostasis, it is not clear
how to inhibit or boost NKX2-1 for the treatment of lung cancer.
This gene is not clearly amplified, overexpressed, or mutated
and as such no clear agonistic or antagonistic molecular targets
of NKX2-1 have been developed for lung cancer.
In order to find potential lung cancer or general thoracic
malignancy-related markers associated with NKX2-1, we
screened other binding partners of NKX2-1, filtering out
known type II pneumocyte and clara cell markers. One of the
interesting binding partners of NKX2-1 is TSHR (12). NKX2-1
binds the promoter of TSHR and promotes constitutive TSHR
expression and TSH/cAMP-induced negative regulation of
TSHR (12,13). Activating and inactivating mutations have
A somatic TSHR mutation in a patient with lung adenocarcinoma
with bronchioloalveolar carcinoma, coronary artery disease
and severe chronic obstructive pulmonary disease
JAMES WAN SOO KIM1, SHARON LEE1, NATALIE LUI1, HELEN CHOI1,2, MICHAEL MULVIHILL1,
LI TAI FANG1, HIO CHUNG KANG2, YONG-WON KWON3, DAVID JABLONS1,2 and IL-JIN KIM1,2
1Thoracic Oncology Laboratory, Department of Surgery, 2Comprehensive Cancer Center, University of California San Francisco,
San Francisco, CA; 3Life Sciences Division, Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA, USA
Received April 4, 2012; Accepted May 14, 2012
Correspondence to: Dr Il-Jin Kim or Dr David Jablons, Department
of Surgery, University of California San Francisco, 2340 Sutter
Street, Room N225, San Francisco, CA 94115, USA
Key words: thyroid stimulating hormone receptor, lung cancer,
KIM et al: TSHR MUTATION IN LUNG ADENOCARCINOMA
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