Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma

Ashton A. Connor, Robert E. Denroche, Gun Ho Jang, Lee Timms, Sangeetha N. Kalimuthu, Iris Selander, Treasa McPherson, Gavin W. Wilson, Michelle A. Chan-Seng-Yue, Ivan Borozan, Vincent Ferretti, Robert C. Grant, Ilinca M. Lungu, Eithne Costello, William Greenhalf, Daniel Palmer, Paula Ghaneh, John P. Neoptolemos, Markus Buchler, Gloria M PetersenSarah Thayer, Michael A. Hollingsworth, Alana Sherker, Daniel Durocher, Neesha Dhani, David Hedley, Stefano Serra, Aaron Pollett, Michael H.A. Roehrl, Prashant Bavi, John M.S. Bartlett, Sean Cleary, Julie M. Wilson, Ludmil B. Alexandrov, Malcolm Moore, Bradly G. Wouters, John D. McPherson, Faiyaz Notta, Lincoln D. Stein, Steven Gallinger

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

IMPORTANCE: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. OBJECTIVE: To classify PDAC according to distinct mutational processes, and explore their clinical significance. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. MAIN OUTCOMES AND MEASURES Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. RESULTS: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes - BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2, 3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. CONCLUSIONS AND RELEVANCE: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

Original languageEnglish (US)
Pages (from-to)774-783
Number of pages10
JournalJAMA oncology
Volume3
Issue number6
DOIs
StatePublished - Jun 1 2017

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Adenocarcinoma
DNA Mismatch Repair
Genome
Immunity
Carcinogenesis
Biomarkers
BRCA2 Gene
CD8-Positive T-Lymphocytes
CTLA-4 Antigen
Indoleamine-Pyrrole 2,3,-Dioxygenase
Neoplasm Metastasis
BRCA1 Gene
RNA Sequence Analysis
Neoplasms
Homologous Recombination
Mutation Rate
Therapeutics
DNA Sequence Analysis
Cluster Analysis
Cohort Studies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Connor, A. A., Denroche, R. E., Jang, G. H., Timms, L., Kalimuthu, S. N., Selander, I., ... Gallinger, S. (2017). Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA oncology, 3(6), 774-783. https://doi.org/10.1001/jamaoncol.2016.3916

Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. / Connor, Ashton A.; Denroche, Robert E.; Jang, Gun Ho; Timms, Lee; Kalimuthu, Sangeetha N.; Selander, Iris; McPherson, Treasa; Wilson, Gavin W.; Chan-Seng-Yue, Michelle A.; Borozan, Ivan; Ferretti, Vincent; Grant, Robert C.; Lungu, Ilinca M.; Costello, Eithne; Greenhalf, William; Palmer, Daniel; Ghaneh, Paula; Neoptolemos, John P.; Buchler, Markus; Petersen, Gloria M; Thayer, Sarah; Hollingsworth, Michael A.; Sherker, Alana; Durocher, Daniel; Dhani, Neesha; Hedley, David; Serra, Stefano; Pollett, Aaron; Roehrl, Michael H.A.; Bavi, Prashant; Bartlett, John M.S.; Cleary, Sean; Wilson, Julie M.; Alexandrov, Ludmil B.; Moore, Malcolm; Wouters, Bradly G.; McPherson, John D.; Notta, Faiyaz; Stein, Lincoln D.; Gallinger, Steven.

In: JAMA oncology, Vol. 3, No. 6, 01.06.2017, p. 774-783.

Research output: Contribution to journalArticle

Connor, AA, Denroche, RE, Jang, GH, Timms, L, Kalimuthu, SN, Selander, I, McPherson, T, Wilson, GW, Chan-Seng-Yue, MA, Borozan, I, Ferretti, V, Grant, RC, Lungu, IM, Costello, E, Greenhalf, W, Palmer, D, Ghaneh, P, Neoptolemos, JP, Buchler, M, Petersen, GM, Thayer, S, Hollingsworth, MA, Sherker, A, Durocher, D, Dhani, N, Hedley, D, Serra, S, Pollett, A, Roehrl, MHA, Bavi, P, Bartlett, JMS, Cleary, S, Wilson, JM, Alexandrov, LB, Moore, M, Wouters, BG, McPherson, JD, Notta, F, Stein, LD & Gallinger, S 2017, 'Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma', JAMA oncology, vol. 3, no. 6, pp. 774-783. https://doi.org/10.1001/jamaoncol.2016.3916
Connor, Ashton A. ; Denroche, Robert E. ; Jang, Gun Ho ; Timms, Lee ; Kalimuthu, Sangeetha N. ; Selander, Iris ; McPherson, Treasa ; Wilson, Gavin W. ; Chan-Seng-Yue, Michelle A. ; Borozan, Ivan ; Ferretti, Vincent ; Grant, Robert C. ; Lungu, Ilinca M. ; Costello, Eithne ; Greenhalf, William ; Palmer, Daniel ; Ghaneh, Paula ; Neoptolemos, John P. ; Buchler, Markus ; Petersen, Gloria M ; Thayer, Sarah ; Hollingsworth, Michael A. ; Sherker, Alana ; Durocher, Daniel ; Dhani, Neesha ; Hedley, David ; Serra, Stefano ; Pollett, Aaron ; Roehrl, Michael H.A. ; Bavi, Prashant ; Bartlett, John M.S. ; Cleary, Sean ; Wilson, Julie M. ; Alexandrov, Ludmil B. ; Moore, Malcolm ; Wouters, Bradly G. ; McPherson, John D. ; Notta, Faiyaz ; Stein, Lincoln D. ; Gallinger, Steven. / Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. In: JAMA oncology. 2017 ; Vol. 3, No. 6. pp. 774-783.
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abstract = "IMPORTANCE: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. OBJECTIVE: To classify PDAC according to distinct mutational processes, and explore their clinical significance. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. MAIN OUTCOMES AND MEASURES Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. RESULTS: The discovery cohort was 53{\%} male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50{\%} male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45{\%}) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes - BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2, 3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. CONCLUSIONS AND RELEVANCE: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.",
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TY - JOUR

T1 - Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma

AU - Connor, Ashton A.

AU - Denroche, Robert E.

AU - Jang, Gun Ho

AU - Timms, Lee

AU - Kalimuthu, Sangeetha N.

AU - Selander, Iris

AU - McPherson, Treasa

AU - Wilson, Gavin W.

AU - Chan-Seng-Yue, Michelle A.

AU - Borozan, Ivan

AU - Ferretti, Vincent

AU - Grant, Robert C.

AU - Lungu, Ilinca M.

AU - Costello, Eithne

AU - Greenhalf, William

AU - Palmer, Daniel

AU - Ghaneh, Paula

AU - Neoptolemos, John P.

AU - Buchler, Markus

AU - Petersen, Gloria M

AU - Thayer, Sarah

AU - Hollingsworth, Michael A.

AU - Sherker, Alana

AU - Durocher, Daniel

AU - Dhani, Neesha

AU - Hedley, David

AU - Serra, Stefano

AU - Pollett, Aaron

AU - Roehrl, Michael H.A.

AU - Bavi, Prashant

AU - Bartlett, John M.S.

AU - Cleary, Sean

AU - Wilson, Julie M.

AU - Alexandrov, Ludmil B.

AU - Moore, Malcolm

AU - Wouters, Bradly G.

AU - McPherson, John D.

AU - Notta, Faiyaz

AU - Stein, Lincoln D.

AU - Gallinger, Steven

PY - 2017/6/1

Y1 - 2017/6/1

N2 - IMPORTANCE: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. OBJECTIVE: To classify PDAC according to distinct mutational processes, and explore their clinical significance. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. MAIN OUTCOMES AND MEASURES Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. RESULTS: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes - BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2, 3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. CONCLUSIONS AND RELEVANCE: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

AB - IMPORTANCE: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. OBJECTIVE: To classify PDAC according to distinct mutational processes, and explore their clinical significance. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. MAIN OUTCOMES AND MEASURES Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. RESULTS: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes - BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2, 3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. CONCLUSIONS AND RELEVANCE: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

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