Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations

Thereasa A. Rich*, Karen L. Reckamp, Young Kwang Chae, Robert C. Doebele, Wade T. Iams, Michael Oh, Victoria M. Raymond, Richard B. Lanman, Jonathan W. Riess, Thomas E. Stinchcombe, Vivek Subbiah, David R. Trevarthen, Stephen Fairclough, Jennifer Yen, Oliver Gautschi

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. Experimental Design: Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68-73 clinically relevant cancer genes. Results: A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. Conclusions: In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance.

Original languageEnglish (US)
Pages (from-to)5832-5842
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number19
DOIs
StatePublished - Jan 1 2019

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DNA
Gene Fusion
Neoplasms
Circulating Neoplastic Cells
Phase II Clinical Trials
Clinical Trials, Phase I
Neoplasm Genes
Missense Mutation
Protein-Tyrosine Kinases
Genes
Thyroid Gland
Breast
Research Design
Nucleotides
Lung
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rich, Thereasa A. ; Reckamp, Karen L. ; Chae, Young Kwang ; Doebele, Robert C. ; Iams, Wade T. ; Oh, Michael ; Raymond, Victoria M. ; Lanman, Richard B. ; Riess, Jonathan W. ; Stinchcombe, Thomas E. ; Subbiah, Vivek ; Trevarthen, David R. ; Fairclough, Stephen ; Yen, Jennifer ; Gautschi, Oliver. / Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 19. pp. 5832-5842.
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title = "Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations",
abstract = "Purpose: RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. Experimental Design: Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68-73 clinically relevant cancer genes. Results: A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. Conclusions: In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance.",
author = "Rich, {Thereasa A.} and Reckamp, {Karen L.} and Chae, {Young Kwang} and Doebele, {Robert C.} and Iams, {Wade T.} and Michael Oh and Raymond, {Victoria M.} and Lanman, {Richard B.} and Riess, {Jonathan W.} and Stinchcombe, {Thomas E.} and Vivek Subbiah and Trevarthen, {David R.} and Stephen Fairclough and Jennifer Yen and Oliver Gautschi",
year = "2019",
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Rich, TA, Reckamp, KL, Chae, YK, Doebele, RC, Iams, WT, Oh, M, Raymond, VM, Lanman, RB, Riess, JW, Stinchcombe, TE, Subbiah, V, Trevarthen, DR, Fairclough, S, Yen, J & Gautschi, O 2019, 'Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations', Clinical Cancer Research, vol. 25, no. 19, pp. 5832-5842. https://doi.org/10.1158/1078-0432.CCR-18-4049

Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations. / Rich, Thereasa A.; Reckamp, Karen L.; Chae, Young Kwang; Doebele, Robert C.; Iams, Wade T.; Oh, Michael; Raymond, Victoria M.; Lanman, Richard B.; Riess, Jonathan W.; Stinchcombe, Thomas E.; Subbiah, Vivek; Trevarthen, David R.; Fairclough, Stephen; Yen, Jennifer; Gautschi, Oliver.

In: Clinical Cancer Research, Vol. 25, No. 19, 01.01.2019, p. 5832-5842.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations

AU - Rich, Thereasa A.

AU - Reckamp, Karen L.

AU - Chae, Young Kwang

AU - Doebele, Robert C.

AU - Iams, Wade T.

AU - Oh, Michael

AU - Raymond, Victoria M.

AU - Lanman, Richard B.

AU - Riess, Jonathan W.

AU - Stinchcombe, Thomas E.

AU - Subbiah, Vivek

AU - Trevarthen, David R.

AU - Fairclough, Stephen

AU - Yen, Jennifer

AU - Gautschi, Oliver

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. Experimental Design: Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68-73 clinically relevant cancer genes. Results: A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. Conclusions: In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance.

AB - Purpose: RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. Experimental Design: Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68-73 clinically relevant cancer genes. Results: A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. Conclusions: In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance.

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U2 - 10.1158/1078-0432.CCR-18-4049

DO - 10.1158/1078-0432.CCR-18-4049

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VL - 25

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

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