Genetic Alterations and Their Clinical Implications in High-Recurrence Risk Papillary Thyroid Cancer
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Purpose Papillary thyroid carcinomas (PTCs) frequently involve genetic alterations. The objective of this study was to investigate genetic alterations and further explore the relationships between these genetic alterations and clinicopathological characteristics in a high-recurrence risk (node positive, N1) PTC group. Materials and Methods Tumor tissue blocks were obtained from 240 surgically resected patients with histologically confirmed stage III/IV (pT3/4 or N1) PTCs. We screened gene fusions using NanoString’s nCounter technology and mutational analysis was performed by direct DNA sequencing. Data describing the clinicopathological characteristics and clinical courses were retrospectively collected. Results Of the 240 PTC patients, 207 (86.3%) had at least one genetic alteration, including BRAF mutation in 190 patients (79.2%), PIK3CAmutation in 25 patients (10.4%), NTRK1/3 fusion in six patients (2.5%), and RET fusion in 24 patients (10.0%). Concomitant presence of more than two genetic alterations was seen in 36 patients (15%). PTCs harboring BRAF mutation were associated with RET wild-type expression (p=0.001). RET fusion genes have been found to occur with significantly higher frequency in N1b stage patients (p=0.003) or groups of patients aged 45 years or older (p=0.031); however, no significant correlation was found between other genetic alterations. There was no trend toward favorable recurrence- free survival or overall survival among patients lacking genetic alterations. Conclusion In the selected high-recurrence risk PTC group, most patients had more than one genetic alteration. However, these known alterations could not entirely account for clinicopathological features of high-recurrence risk PTC.
Abstract
Purpose Papillary thyroid carcinomas (PTCs) frequently involve genetic alterations. The objective of this study was to investigate genetic alterations and further explore the relationships between these genetic alterations and clinicopathological characteristics in a high-recurrence risk (node positive, N1) PTC group. Materials and Methods Tumor tissue blocks were obtained from 240 surgically resected patients with histologically confirmed stage III/IV (pT3/4 or N1) PTCs. We screened gene fusions using NanoString’s nCounter technology and mutational analysis was performed by direct DNA sequencing. Data describing the clinicopathological characteristics and clinical courses were retrospectively collected. Results Of the 240 PTC patients, 207 (86.3%) had at least one genetic alteration, including BRAF mutation in 190 patients (79.2%), PIK3CAmutation in 25 patients (10.4%), NTRK1/3 fusion in six patients (2.5%), and RET fusion in 24 patients (10.0%). Concomitant presence of more than two genetic alterations was seen in 36 patients (15%). PTCs harboring BRAF mutation were associated with RET wild-type expression (p=0.001). RET fusion genes have been found to occur with significantly higher frequency in N1b stage patients (p=0.003) or groups of patients aged 45 years or older (p=0.031); however, no significant correlation was found between other genetic alterations. There was no trend toward favorable recurrence- free survival or overall survival among patients lacking genetic alterations. Conclusion In the selected high-recurrence risk PTC group, most patients had more than one genetic alteration. However, these known alterations could not entirely account for clinicopathological features of high-recurrence risk PTC.
참고문헌 (29)
- Ito Y, "Increasing incidence of thyroid cancer : controversies explored", Nat Rev Endocrinol, 9, pp.178~184 (2013)
- 김원배, "A Closer Look at Papillary Thyroid Carcinoma Won Bae", Endocrinology and Metabolism, 30(1), pp.1~6 (2015), 대한내분비학회
- Henderson YC, "High rate of BRAF and RET", PTC dual mutations associated with recurrent papillary thyroid carcinoma, 2009, pp.15, 485~491
- Xing M, "Molecular pathogenesis and mechanisms of thyroid cancer", Nat Rev Cancer, 13, pp.184~199 (2013)
- Soares P, "BRAF mutations and RET", PTC rearrangements are alternative events in the etiopathogenesis of PTC, 2003, pp.22, 4578~4580
- Adeniran AJ, "Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas", Am J Surg Pathol, 30, pp.216~222 (2006)
- Costa AM, "BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma", Clin Endocrinol(Oxf), 68, pp.618~634 (2008)
- 홍아람, "The Frequency and Clinical Implications of the BRAFV600E Mutation in Papillary Thyroid Cancer Patients in Korea Over the Past Two Decades", Endocrinology and Metabolism, 29(4), pp.505~513 (2014), 대한내분비학회
- Kim TH, "The association of the BRAF(V600E)mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer : a meta-analysis", Cancer, 118, pp.1764~1773 (2012)
- Xing M, "Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer", JAMA, 309, pp.1493~1501 (2013)
- Benvenga S, "Molecular pathways associated with aggressiveness of papillary thyroid cancer", Curr Genomics, 15, pp.162~170 (2014)
- 송영신, "Mutation Profile of Well-Differentiated Thyroid Cancer in Asians", Endocrinology and Metabolism, 30(3), pp.252~262 (2015), 대한내분비학회
- Xing M, "Genetic alterations in the phosphatidylinositol-3kinase", Akt pathway in thyroid cancer, 2010, pp.20, 697~706
- Stransky N, "The landscape of kinase fusions in cancer", Nat Commun, 5, pp.4846~ (2014)
- Cancer Genome Atlas Research Network, "Integrated genomic characterization of papillary thyroid carcinoma", Cell, 159, pp.676~690 (2014)
- Greco A, "Rearrangements of NTRK1gene in papillary thyroid carcinoma", Mol Cell Endocrinol, 321, pp.44~49 (2010)
- Cho BY, "Changes in the clinicopathological characteristics and outcomes of thyroid cancer in Korea over the past four decades", Thyroid, 23, pp.797~804 (2013)
- Chitikova Z, "Identification of new biomarkers for human papillary thyroid carcinoma employing NanoString analysis", Oncotarget, 6, pp.10978~10993 (2015)
- He G, "Prognostic value of the BRAF V600E mutation in papillary thyroid carcinoma", Oncol Lett, 7, pp.439~443 (2014)
- Cheng SP, "Significance of allelic percentage of BRAF c.1799T > A (V600E) mutation in papillary thyroid carcinoma", Ann Surg Oncol, 21(Suppl 4), pp.S619~S626 (2014)
- Li C, "BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer : a meta-analysis", J Clin Endocrinol Metab, 97, pp.4559~4570 (2012)
- Xing M, "Association between BRAF V600E mutation and recurrence of papillary thyroid cancer", J Clin Oncol, 33, pp.42~50 (2015)
- Henke LE, "BRAF mutation is not predictive of long-term outcome in papillary thyroid carcinoma", Cancer Med, 4, pp.791~799 (2015)
- Howell GM, "RAS mutations in thyroid cancer", Oncologist, 18, pp.926~932 (2013)
- Ricarte-Filho JC, "Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1", Cancer Res, 69, pp.4885~4893 (2009)
- Pennelli G, "BRAF(K601E)mutation in a patient with a follicular thyroid carcinoma", Thyroid, 21, pp.1393~1396 (2011)
- Mulligan LM, "RET revisited : expanding the oncogenic portfolio", Nat Rev Cancer, 14, pp.173~186 (2014)
- Zou M, "Concomitant RAS, RET", PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma, 2014, pp.24, 1256~1266
- Guerra A, "Concomitant BRAF(V600E)mutation and RET", PTC rearrangement is a frequent occurrence in papillary thyroid carcinoma, 2014, pp.24, 254~259