Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times

Somak Roy, William A. LaFramboise, Ta Chiang Liu, Dengfeng Cao, Alyssa Luvison, Caitlyn Miller, Maureen A. Lyons, Roderick J. O'Sullivan, Amer H. Zureikat, Melissa E. Hogg, Allan Tsung, Kenneth K. Lee, Nathan Bahary, Randall E. Brand, Jennifer S. Chennat, Kenneth E. Fasanella, Kevin McGrath, Marina N. Nikiforova, Georgios I. Papachristou, Adam SlivkaHerbert J. Zeh, Aatur D. Singhi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.

Original languageEnglish (US)
Pages (from-to)2060-2063.e8
JournalGastroenterology
Volume154
Issue number8
DOIs
StatePublished - Jun 2018
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase Inhibitor p16
Chromatin Assembly and Disassembly
Neuroendocrine Tumors
Chromatin
Neoplasm Metastasis
Survival
Proteins
Lysine
Exome
Multiple Endocrine Neoplasia Type 1
DNA-Binding Proteins
Transferases
Genes
Disease-Free Survival
ATR-X syndrome
Mutation
DNA

Keywords

  • Pancreas
  • Prognosis
  • Prognostic Factor
  • Risk

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times. / Roy, Somak; LaFramboise, William A.; Liu, Ta Chiang; Cao, Dengfeng; Luvison, Alyssa; Miller, Caitlyn; Lyons, Maureen A.; O'Sullivan, Roderick J.; Zureikat, Amer H.; Hogg, Melissa E.; Tsung, Allan; Lee, Kenneth K.; Bahary, Nathan; Brand, Randall E.; Chennat, Jennifer S.; Fasanella, Kenneth E.; McGrath, Kevin; Nikiforova, Marina N.; Papachristou, Georgios I.; Slivka, Adam; Zeh, Herbert J.; Singhi, Aatur D.

In: Gastroenterology, Vol. 154, No. 8, 06.2018, p. 2060-2063.e8.

Research output: Contribution to journalArticle

Roy, S, LaFramboise, WA, Liu, TC, Cao, D, Luvison, A, Miller, C, Lyons, MA, O'Sullivan, RJ, Zureikat, AH, Hogg, ME, Tsung, A, Lee, KK, Bahary, N, Brand, RE, Chennat, JS, Fasanella, KE, McGrath, K, Nikiforova, MN, Papachristou, GI, Slivka, A, Zeh, HJ & Singhi, AD 2018, 'Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times', Gastroenterology, vol. 154, no. 8, pp. 2060-2063.e8. https://doi.org/10.1053/j.gastro.2018.02.026
Roy, Somak ; LaFramboise, William A. ; Liu, Ta Chiang ; Cao, Dengfeng ; Luvison, Alyssa ; Miller, Caitlyn ; Lyons, Maureen A. ; O'Sullivan, Roderick J. ; Zureikat, Amer H. ; Hogg, Melissa E. ; Tsung, Allan ; Lee, Kenneth K. ; Bahary, Nathan ; Brand, Randall E. ; Chennat, Jennifer S. ; Fasanella, Kenneth E. ; McGrath, Kevin ; Nikiforova, Marina N. ; Papachristou, Georgios I. ; Slivka, Adam ; Zeh, Herbert J. ; Singhi, Aatur D. / Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times. In: Gastroenterology. 2018 ; Vol. 154, No. 8. pp. 2060-2063.e8.
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abstract = "Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50{\%} of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75{\%}) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81{\%} of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39{\%} survived disease-free for 5 years and 44{\%} had disease-specific survival times of 10 years. Among patients without any of these alterations, 98{\%} survived disease-free for 5 years and 95{\%} had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.",
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T1 - Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times

AU - Roy, Somak

AU - LaFramboise, William A.

AU - Liu, Ta Chiang

AU - Cao, Dengfeng

AU - Luvison, Alyssa

AU - Miller, Caitlyn

AU - Lyons, Maureen A.

AU - O'Sullivan, Roderick J.

AU - Zureikat, Amer H.

AU - Hogg, Melissa E.

AU - Tsung, Allan

AU - Lee, Kenneth K.

AU - Bahary, Nathan

AU - Brand, Randall E.

AU - Chennat, Jennifer S.

AU - Fasanella, Kenneth E.

AU - McGrath, Kevin

AU - Nikiforova, Marina N.

AU - Papachristou, Georgios I.

AU - Slivka, Adam

AU - Zeh, Herbert J.

AU - Singhi, Aatur D.

PY - 2018/6

Y1 - 2018/6

N2 - Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.

AB - Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.

KW - Pancreas

KW - Prognosis

KW - Prognostic Factor

KW - Risk

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