Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality

Rengyun Liu, Justin Bishop, Guangwu Zhu, Tao Zhang, Paul W. Ladenson, Mingzhao Xing

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

IMPORTANCE BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established. OBJECTIVE To establish the prognostic power of this genetic duet in PTC-specific mortality. DESIGN, SETTING, AND PARTICIPANTS This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1, 295, 228C>T and chr5:1, 295, 250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years). MAIN OUTCOMES AND MEASURES BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC. RESULTS Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6%) with neither mutation 7 of 292 (2.4%) with BRAF V600E alone 4 of 64 (6.3%) with TERT promoter mutation alone and 15 of 66 (22.7%) with the genetic duet and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95%CI, 0.30-2.13), 3.08 (95%CI, 1.47-6.46), 6.62 (95%CI, 2.48-17.64), and 29.86 (95%CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95%CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone 8.18 (2.04-32.75) with TERT mutation alone and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34 95%CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46 95%CI, 12.26-241.82), which remained strongly significant (HR, 18.56 95%CI, 2.97-116.18) after adjustment for clinicopathological factors. CONCLUSIONS AND RELEVANCE These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>>>>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk.

Original languageEnglish (US)
Pages (from-to)202-208
Number of pages7
JournalJAMA oncology
Volume3
Issue number2
DOIs
StatePublished - Feb 1 2017

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Thyroid Neoplasms
Mutation
Mortality
Papillary Thyroid cancer
Factor IX
Kaplan-Meier Estimate

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality. / Liu, Rengyun; Bishop, Justin; Zhu, Guangwu; Zhang, Tao; Ladenson, Paul W.; Xing, Mingzhao.

In: JAMA oncology, Vol. 3, No. 2, 01.02.2017, p. 202-208.

Research output: Contribution to journalArticle

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title = "Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality",
abstract = "IMPORTANCE BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established. OBJECTIVE To establish the prognostic power of this genetic duet in PTC-specific mortality. DESIGN, SETTING, AND PARTICIPANTS This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1, 295, 228C>T and chr5:1, 295, 250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years). MAIN OUTCOMES AND MEASURES BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC. RESULTS Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6{\%}) with neither mutation 7 of 292 (2.4{\%}) with BRAF V600E alone 4 of 64 (6.3{\%}) with TERT promoter mutation alone and 15 of 66 (22.7{\%}) with the genetic duet and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95{\%}CI, 0.30-2.13), 3.08 (95{\%}CI, 1.47-6.46), 6.62 (95{\%}CI, 2.48-17.64), and 29.86 (95{\%}CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95{\%}CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone 8.18 (2.04-32.75) with TERT mutation alone and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34 95{\%}CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46 95{\%}CI, 12.26-241.82), which remained strongly significant (HR, 18.56 95{\%}CI, 2.97-116.18) after adjustment for clinicopathological factors. CONCLUSIONS AND RELEVANCE These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>>>>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk.",
author = "Rengyun Liu and Justin Bishop and Guangwu Zhu and Tao Zhang and Ladenson, {Paul W.} and Mingzhao Xing",
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T1 - Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality

AU - Liu, Rengyun

AU - Bishop, Justin

AU - Zhu, Guangwu

AU - Zhang, Tao

AU - Ladenson, Paul W.

AU - Xing, Mingzhao

PY - 2017/2/1

Y1 - 2017/2/1

N2 - IMPORTANCE BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established. OBJECTIVE To establish the prognostic power of this genetic duet in PTC-specific mortality. DESIGN, SETTING, AND PARTICIPANTS This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1, 295, 228C>T and chr5:1, 295, 250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years). MAIN OUTCOMES AND MEASURES BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC. RESULTS Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6%) with neither mutation 7 of 292 (2.4%) with BRAF V600E alone 4 of 64 (6.3%) with TERT promoter mutation alone and 15 of 66 (22.7%) with the genetic duet and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95%CI, 0.30-2.13), 3.08 (95%CI, 1.47-6.46), 6.62 (95%CI, 2.48-17.64), and 29.86 (95%CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95%CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone 8.18 (2.04-32.75) with TERT mutation alone and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34 95%CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46 95%CI, 12.26-241.82), which remained strongly significant (HR, 18.56 95%CI, 2.97-116.18) after adjustment for clinicopathological factors. CONCLUSIONS AND RELEVANCE These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>>>>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk.

AB - IMPORTANCE BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established. OBJECTIVE To establish the prognostic power of this genetic duet in PTC-specific mortality. DESIGN, SETTING, AND PARTICIPANTS This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1, 295, 228C>T and chr5:1, 295, 250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years). MAIN OUTCOMES AND MEASURES BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC. RESULTS Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6%) with neither mutation 7 of 292 (2.4%) with BRAF V600E alone 4 of 64 (6.3%) with TERT promoter mutation alone and 15 of 66 (22.7%) with the genetic duet and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95%CI, 0.30-2.13), 3.08 (95%CI, 1.47-6.46), 6.62 (95%CI, 2.48-17.64), and 29.86 (95%CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95%CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone 8.18 (2.04-32.75) with TERT mutation alone and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34 95%CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46 95%CI, 12.26-241.82), which remained strongly significant (HR, 18.56 95%CI, 2.97-116.18) after adjustment for clinicopathological factors. CONCLUSIONS AND RELEVANCE These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>>>>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk.

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