|Year : 2017 | Volume
| Issue : 1 | Page : 36-41
|Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer
Seo Yun Kim1, Hye-Ryoun Kim1, Cheol Hyeon Kim1, Jae Soo Koh2, Hee Jong Baek3, Chang-Min Choi4, Joon Seon Song5, Jae Cheol Lee6, Im Il Na7
1 Department of Internal Medicine, Division of Pulmonology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
2 Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
3 Department of Thoracic Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
4 Department of Pulmonology and Critical Care Medicine; Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Ulsan, Republic of Korea
5 Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Ulsan, Republic of Korea
6 Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Ulsan, Republic of Korea
7 Department of Internal Medicine, Division of Hematology/Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
|Date of Submission||04-Jul-2016|
|Date of Acceptance||14-Sep-2016|
|Date of Web Publication||6-Jan-2017|
Im Il Na
Department of Internal Medicine, Korea Cancer Center Hospital, 75, Nowon-gil, Nowon-gu, Seoul 139-706
Republic of Korea
| Abstract|| |
BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC).
METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models.
RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P < 0.001), EGFR mutations were positively associated with a personal history of thyroid cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023).
CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.
Keywords: Epidermal growth factor receptor, female, nonsmall cell lung carcinoma, thyroid neoplasm
|How to cite this article:|
Kim SY, Kim HR, Kim CH, Koh JS, Baek HJ, Choi CM, Song JS, Lee JC, Na II. Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer. Ann Thorac Med 2017;12:36-41
|How to cite this URL:|
Kim SY, Kim HR, Kim CH, Koh JS, Baek HJ, Choi CM, Song JS, Lee JC, Na II. Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer. Ann Thorac Med [serial online] 2017 [cited 2017 Jul 22];12:36-41. Available from: http://www.thoracicmedicine.org/text.asp?2017/12/1/36/197774
Lung cancer is the leading cause of cancer-related death worldwide, with 159,260 expected deaths in the United States in 2014.  It is estimated that 72,330 women will die from progressive lung cancer, accounting for 26% of all cancer-related deaths among women in the United States.  Lung cancer incidence has increased 4-fold in women over the past thirty years, until 2000.  Epidemiological data demonstrated sex-specific differences in lung cancer.  In Asian populations, 60%-80% of women with lung cancer have never smoked, in contrast to 10%-15% of men with lung cancer. 
Epidermal growth factor receptor (EGFR) has been one of the targets in the era of individualized therapy for nonsmall cell lung cancer (NSCLC), leading to improvements in survival outcomes and quality of life for patients with tumors harboring EGFR mutations,  which are predominantly found in women. Other factors associated with EGFR mutation are adenocarcinoma histology, no history of smoking, and Asian background. ,, Recently, a Chinese group reported that multiple primary malignancies occurred more frequently in lung adenocarcinoma patients with EGFR mutations.  However, the cohort has included men, whose patterns of cancer history are different from those in women. In the previous study,  exclusion of recurred lung cancer has remained uncertain. Thus, in female lung cancer patients, the association between the EGFR mutations and history of malignancies is unknown.
Thyroid cancer, one of the predominant malignancies in women, is the most common cancer of the endocrine system, and its incidence has been increasing rapidly worldwide.  It is estimated that approximately 47,790 new cases of thyroid cancer will be diagnosed in women in the United States in 2014.  Epidemiologic studies have reported that the risk of secondary primary lung cancer after thyroid cancer is significantly increased in women. , The EGFR pathway has been proposed to be important for thyroid cancer proliferation and metastasis. ,, In laboratory studies, EGFR mutation and overexpression have been detected in thyroid cancer. ,, In addition, Masago et al. showed that EGFR mutations commonly found in pulmonary adenocarcinoma were also detected in 7 (30.4%) of 23 patients with Japanese papillary thyroid cancer. 
Previously, in addition to aggregation of cancer in first relatives of lung cancer patients,  the association between family history of cancer and EGFR mutational status has been investigated. , Recent studies have suggested the increased incidence of EGFR mutations in patients with family history of all kinds of cancer. , However, the prevalence of EGFR mutation according to family history of thyroid cancer has not been reported.
Based on these findings, we conducted this retrospective study to investigate the association between EGFR mutation and thyroid cancer in terms of patient's personal history as well as familial history in female NSCLC.
| Methods|| |
This retrospective study included female patients who were diagnosed with NSCLC histologically or cytologically and underwent an EGFR mutation test between June 2003 and August 2013 at the Korea Cancer Center Hospital and the Asan Medical Center. To be eligible for inclusion, patients needed to have a documented EGFR status at the time of diagnosis, which was identified from the NSCLC pathology database of each institution. Informed consent for genetic tests was also required.
The demographic and clinical characteristics, including age at diagnosis of lung cancer, smoking status, and subtype of NSCLC histology, were reviewed from the medical records. We included patients with NSCLC, whose pathological findings were complemented with additional immunohistochemical staining when appropriate. We routinely asked patients about personal and family history of malignancy when patients were admitted for workup of lung cancer. The personal history of nonpulmonary malignancy and the family history of cancers among first-degree relatives of the patients were collected from the medical records retrospectively. To exclude the impact of sex and previous lung cancer, this study was confined to female patients who received an initial diagnosis with NSCLC during the study period. Primary lung cancer was confirmed by pathology review with additional immunohistochemistry staining and clinical review, especially in patients who were diagnosed with other cancer concurrently with the diagnosis of lung cancer. , This study was approved by our Institutional Review Board.
Epidermal growth factor receptor genotyping
Genomic DNA was extracted from paraffin-embedded tissues, as described previously.  In patients whose only available tissue was the cytological sample at initial diagnosis, methanol-fixed cytological specimens were used for DNA extraction.  EGFR mutation analysis was carried out by direct sequencing (n = 571) or pyrosequencing (n = 264), using previously described methods. ,, The presence of EGFR mutations was determined by evaluating exons 18, 19, 20, and 21.
The associations between EGFR mutation status and clinicopathological parameters, such as age, smoking status, histology, EGFR mutation status, personal history of other cancer, and family history of cancer were compared using the χ2 test for categorical variables and t-test for continuous variables. The odds ratios for the risk of EGFR mutation were analyzed using a multivariate logistic regression model, including age, smoking status, histology (adenocarcinoma vs. nonadenocarcinoma), stage, personal history of thyroid and nonthyroid cancer, and family history of thyroid and nonthyroid cancer. A two-sided alpha level of 0.05 was used to indicate statistical significance. All statistical analyses were carried out using SPSS software (version 18.0; SPSS, Inc., Chicago, IL, USA).
| Results|| |
Epidermal growth factor receptor mutation and clinical features
A total of 835 female patients who satisfied the inclusion criteria were identified in the study. The clinical characteristics of the study population are summarized in [Table 1]. The mean age was 60.0 ± 11.7 years, and most individuals had never been smokers (93.4%). The major histologic type was adenocarcinoma (744 cases), followed by squamous (38), adenosquamous (9), large cell (4), and other (39) carcinoma types.
|Table 1: Relationship between epidermal growth factor receptor mutation and clinical factors |
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Three hundred and seventy-eight (45.3%) of the 835 patients had EGFR mutations. The most prevalent EGFR mutations were in-frame deletions of exon 19 (263 patients, 69.8%), followed by L858R substitution in exon 21 (105 patients, 27.9%). The remaining ten patients (2.6%) had a G719X mutation in exon 18.
The frequency of EGFR mutation was significantly higher in patients with adenocarcinoma than in those with nonadenocarcinoma tumors (48.0% vs. 23.1%, P < 0.001). EGFR mutation was more common in never-smokers than ever-smokers, but the difference was not statistically significant (46.2% vs. 32.7%; P = 0.053). The differences in age (mean age ± standard deviation, 60.6 ± 11.0 years vs. 59.4 ± 12.2 years, P = 0.126) according to EGFR mutation did not reach statistical significance. A different incidence of EGFR mutation according to stage was observed (51.5% [I/II] vs. 35.4% [III] vs. 44.8% [IV], P = 0.013).
Association of epidermal growth factor receptor mutation with thyroid cancer and a family history of thyroid cancer
Ninety-eight (11.7%) of the 835 patients had a personal history of cancer. Of these, 34 (4.1%) had thyroid cancer and 63 (7.5%) nonthyroid cancers. Of the 63 patients with nonthyroid cancers, 22 (2.6%) had cervical cancers, 16 (1.9%) breast cancers, 9 (1.1%) colon cancers, 6 (0.7%) gastric cancers, and 16 (1.9%) other cancers. Of the 34 thyroid cancer patients, 17 (50%) were diagnosed with thyroid cancer concurrently with the diagnosis of lung cancer, while 10 (29.4%) were diagnosed with thyroid cancer within 5 years before the diagnosis of lung cancer. The median time from the diagnosis of thyroid cancer to the diagnosis of lung cancer was 6 months (range: 0-40 years), and was not associated with EGFR mutations (data not shown). Two hundred and eighty-two (34.1%) of the 835 patients had a family history of cancer among first-degree relatives. Of these, 15 (1.8%) had thyroid cancer and 259 (31.0%) nonthyroid cancers. Of the 259 patients with nonthyroid cancers, 72 (8.6%) had lung cancer, 68 (8.4%) gastric cancer, 49 (6.0%) hepatocellular carcinoma, 30 (3.7%) colon cancer, 27 (3.3%) cervical cancer, 20 (2.4%) breast cancer, and 72 (8.9%) other cancers.
The presence of EGFR mutations was positively associated with a personal history of thyroid cancer (5.8% vs. 2.6%; P = 0.020) [Table 1], while it showed a trend toward inverse association with personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Interestingly, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while it showed a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066).
When we evaluated the association of thyroid cancer on EGFR mutations using a multivariate model including age, smoking history, histology and stage, overall different effect between personal history of thyroid and nonthyroid cancers on EGFR mutation was maintained [P = 0.035, [Table 2]. In further statistical evaluation, EGFR mutation was positively related with thyroid cancer and inversely associated with nonthyroid cancer like as univariate analysis. However, analysis of each variable did not reach statistical significance (P = 0.050 for thyroid cancer and P = 0.118 for nonthyroid cancer, respectively). In addition, the statistical difference in the incidence of EGFR mutations in patients with a family history of thyroid versus nonthyroid cancer remained significant (P = 0.023). There were also similar trends between family history of thyroid cancer and nonthyroid cancer on EGFR mutation like as univariate analysis, but they did not show significant difference (P = 0.067 for thyroid cancer and P = 0.060 for nonthyroid cancer, respectively).
|Table 2: Multivariate analysis for epidermal growth factor receptor mutation in female nonsmall - cell lung cancer |
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| Discussion|| |
This is the first study to evaluate the possibility of an association of EGFR mutations with thyroid cancer and a family history of thyroid cancer in female patients with NSCLC. The frequency of EGFR mutation was consistent with previous reports. , Association of smoking history with histology has also been observed in recent studies of female lung cancer. , Interestingly, EGFR mutations were more prevalent in patients with thyroid cancer or a family history of thyroid cancer. These associations remained significant in a multivariate analysis.
Recent studies supported the idea of a high likelihood of EGFR mutations in female patients with thyroid cancer. An epidemiological study investigated the incidence and types of second primary malignancies in Korean patients with thyroid cancer. Among 178,844 patients with thyroid cancer from the Korea Central Cancer Registry database, the overall risk of lung cancer calculated by the standardized incidence ratio (SIR) according to the number of cancer events was elevated (SIR = 1.35, 95% confidence interval [CI]: 1.22-1.50). The risk of lung cancer events among women with thyroid cancer was significantly increased (SIR = 1.58, 95% CI: 1.40-1.78), whereas it was not increased in male patients (SIR = 0.95; 95% CI: 0.77-1.17).  In another population-based study based on the Taiwan Cancer Registry, a significantly elevated risk of lung cancer was found after thyroid cancer was observed in women (SIR = 1.80, 95% CI: 1.37-2.34), but not in men (SIR = 1.24, 95% CI: 0.82-1.80).  Interestingly, a trend toward inverse association with EGFR mutation was observed in nonthyroid cancer, which is inconsistent with a previous study, which reported that EGFR mutations were frequently found in multiple primary cancers.  This discrepancy may be caused by the different study population. Our study population was sex-specific, dealing with only female patients, while previous studies included both male and female patients.
It is uncertain how thyroid cancer affects EGFR mutation in female patients with NSCLC. However, there are several explanations for the association between EGFR mutation and thyroid cancer. First, recent studies suggest that estrogen is involved in the pathogenesis of thyroid cancer and lung cancer in females. , Estrogen is a potent growth factor both for benign and malignant thyroid cells that may explain the sex difference in the prevalence of thyroid nodules and thyroid cancer. Estrogen is also involved in the regulation of angiogenesis and metastasis that are critical for the outcome of thyroid cancer.  Laboratory studies of lung cancer suggest that estrogen receptor may act in conjunction with EGFR in carcinogenesis.  Furthermore, strong nuclear expression of estrogen receptor beta has been detected in EGFR mutated tumors.  Second, we suggest that thyroid transcription factor 1 (TTF-1) might play a certain role. Parental cells of lung and thyroid cancer have similar developmental properties. The progenitor cells of lung and thyroid originate from the embryonic foregut endoderm,  and the process of organogenesis requires NK2 homeobox 1 (NKX2-1), also known as TTF-1. , Several studies showed that NKX2-1 is amplified in lung cancer, implying that NKX2-1 is likely functionally relevant to the pulmonary tumorigenic process.  It should be noted that TTF-1 was predominantly expressed in EGFR mutated lung adenocarcinoma.  Interestingly, altered expression of TTF-1 was observed in thyroid tumors. 
This study is the first to report the association of EGFR mutations in lung cancer cells with a family history of thyroid cancer in women. Inconsistent results with previous studies could be attributed to heterogeneous populations, as well as different accuracies in reporting family cancer history between men and women. , The mechanism of the impact of family history of thyroid or of any cancer on the incidence of EGFR mutation is still unknown. A recent report described a family with multiple cases of NSCLC associated with germ line transmission of EGFR T790M gene mutation.  The presence of this mutation in a case of familial clustering of NSCLC could have a role in the inherited susceptibility to NSCLC. However, its significance in thyroid cancer is unknown. Rather, inherited single nucleotide polymorphisms of NKX2-1, a potential genetic risk factor for papillary thyroid cancer,  may play a role in the pathogenesis of EGFR-mutated tumors.
The current study has several limitations. First, all studies relied on self-report of family history and thus had the potential for a recall bias. The limited knowledge or errors of their family history of cancer will result in a false family history. Second, in some patients diagnosed with thyroid cancer before the diagnosis of lung cancer, the histologic type (papillary thyroid carcinoma, follicular thyroid carcinoma, and anaplastic thyroid carcinoma, and others) was unknown. Third, the detailed information on age and the number of first-degree relatives could not be analyzed in this retrospective study. Finally, because of retrospective nature, our findings about the relation between thyroid cancer and the incidence of EGFR mutation need external validation through further studies.
| Conclusions|| |
We found that thyroid cancer and a family history of thyroid cancer are common in female NSCLC patients with EGFR mutation. Although the pathogenesis of EGFR mutated NSCLC has not been understood yet, the fact that thyroid cancer relates to EGFR mutation in NSCLC might provide a clue to the pathogenesis of this genetic change.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]