Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma

被引：50

作者：

Grant, Robert C. ^{[1
,2
]}

Denroche, Robert ^{[1
]}

Jang, Gun Ho ^{[1
]}

Nowak, Klaudia M. ^{[3
]}

Zhang, Amy ^{[1
]}

Borgida, Ayelet ^{[4
]}

Holter, Spring ^{[4
]}

Topham, James T. ^{[5
]}

Wilson, Julie ^{[1
]}

Dodd, Anna ^{[2
]}

Jang, Raymond ^{[2
]}

Prince, Rebecca ^{[2
]}

Karasinska, Joanna M. ^{[5
]}

Schaeffer, David F. ^{[5
]}

Wang, Yifan ^{[6
]}

Zogopoulos, George ^{[6
]}

Berry, Scott ^{[7
]}

Simeone, Diane ^{[8
]}

Renouf, Daniel J. ^{[5
,9
]}

Notta, Faiyaz ^{[1
]}

O'Kane, Grainne ^{[2
]}

Knox, Jennifer ^{[2
]}

Fischer, Sandra ^{[3
]}

Gallinger, Steven ^{[1
,2
,4
]}

机构：

[1] Ontario Inst Canc Res, Toronto, ON, Canada

[2] Princess Margaret Hosp Canc Ctr, Wallace McCain Ctr Pancreat Canc, Toronto, ON, Canada

[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[4] Mt Sinai Hosp, Ontario Pancreas Canc Study, Toronto, ON, Canada

[5] Pancreas Ctr BC, Vancouver, BC, Canada

[6] Goodman Canc Res Ctr, Montreal, PQ, Canada

[7] Queens Univ, Dept Oncol, Kingston, ON, Canada

[8] NYU Langone Hlth, New York, NY USA

[9] BC Canc Agcy, Vancouver, BC, Canada

来源：

GUT | 2021年 / 70卷 / 10期

关键词：

TUMOR MICROSATELLITE-INSTABILITY; CANCER PREDISPOSITION GENES; GERMLINE MUTATIONS; ASSOCIATION; GEMCITABINE; PREVALENCE; FOLFIRINOX; SIGNATURES;

D O I：

10.1136/gutjnl-2020-320730

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Objective To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP). Design We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)). Results 12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity. Conclusions MMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

引用

页码：1894 / 1903

页数：10

共 55 条

[1] Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine [J].

Aguirre, Andrew J. ;

Nowak, Jonathan A. ;

Camarda, Nicholas D. ;

Moffitt, Richard A. ;

Ghazani, Arezou A. ;

Hazar-Rethinam, Mehlika ;

Raghavan, Srivatsan ;

Kim, Jaegil ;

Brais, Lauren K. ;

Ragon, Dorisanne ;

Welch, Marisa W. ;

Reilly, Emma ;

McCabe, Devin ;

Marini, Lori ;

Anderka, Kristin ;

Helvie, Karla ;

Oliver, Nelly ;

Babic, Ana ;

Da Silva, Annacarolina ;

Nadres, Brandon ;

Van Seventer, Emily E. ;

Shahzade, Heather A. ;

St Pierre, Joseph P. ;

Burke, Kelly P. ;

Clancy, Thomas ;

Cleary, James M. ;

Doyle, Leona A. ;

Jajoo, Kunal ;

McCleary, Nadine J. ;

Meyerhardt, Jeffrey A. ;

Murphy, Janet E. ;

Ng, Kimmie ;

Patel, Anuj K. ;

Perez, Kimberly ;

Rosenthal, Michael H. ;

Rubinson, Douglas A. ;

Ryou, Marvin ;

Shapiro, Geoffrey I. ;

Sicinska, Ewa ;

Silverman, Stuart G. ;

Nagy, Rebecca J. ;

Lanman, Richard B. ;

Knoerzer, Deborah ;

Welsch, Dean J. ;

Yurgelun, Matthew B. ;

Fuchs, Charles S. ;

Garraway, Levi A. ;

Getz, Gad ;

Hornick, Jason L. ;

Johnson, Bruce E. .

CANCER DISCOVERY, 2018, 8 (09) :1096-1111

[2] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[3] Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial [J].

Aung, Kyaw L. ;

Fischer, Sandra E. ;

Denroche, Robert E. ;

Jang, Gun-Ho ;

Dodd, Anna ;

Creighton, Sean ;

Southwood, Bernadette ;

Liang, Sheng-Ben ;

Chadwick, Dianne ;

Zhang, Amy ;

O'Kane, Grainne M. ;

Albaba, Hamzeh ;

Moura, Shari ;

Grant, Robert C. ;

Miller, Jessica K. ;

Mbabaali, Faridah ;

Pasternack, Danielle ;

Lungu, Ilinca M. ;

Bartlett, John M. S. ;

Ghai, Sangeet ;

Lemire, Mathieu ;

Holter, Spring ;

Connor, Ashton A. ;

Moffitt, Richard A. ;

Yeh, Jen Jen ;

Timms, Lee ;

Krzyzanowski, Paul M. ;

Dhani, Neesha ;

Hedley, David ;

Notta, Faiyaz ;

Wilson, Julie M. ;

Moore, Malcolm J. ;

Gallinger, Steven ;

Knox, Jennifer J. .

CLINICAL CANCER RESEARCH, 2018, 24 (06) :1344-1354

[4] IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade [J].

Ayers, Mark ;

Lunceford, Jared ;

Nebozhyn, Michael ;

Murphy, Erin ;

Loboda, Andrey ;

Kaufman, David R. ;

Albright, Andrew ;

Cheng, Jonathan D. ;

Kang, S. Peter ;

Shankaran, Veena ;

Piha-Paul, Sarina A. ;

Yearley, Jennifer ;

Seiwert, Tanguy Y. ;

Ribas, Antoni ;

McClanahan, Terrill K. .

JOURNAL OF CLINICAL INVESTIGATION, 2017, 127 (08) :2930-2940

[5] Management of pancreatic adenocarcinoma in Ontario, Canada: a population-based study using novel case ascertainment [J].

Borgida, Ayelet Eppel ;

Ashamalla, Shady ;

Al-Sukhni, Wigdan ;

Rothenmund, Heidi ;

Urbach, David ;

Moore, Malcolm ;

Cotterchio, Michelle ;

Gallinger, Steven .

CANADIAN JOURNAL OF SURGERY, 2011, 54 (01) :54-60

[6] Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples [J].

Cibulskis, Kristian ;

Lawrence, Michael S. ;

Carter, Scott L. ;

Sivachenko, Andrey ;

Jaffe, David ;

Sougnez, Carrie ;

Gabriel, Stacey ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2013, 31 (03) :213-219

[7] Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Patients With Pancreatic Ductal Adenocarcinoma [J].

Cloyd, Jordan M. ;

Katz, Matthew H. G. ;

Wang, Huamin ;

Cuddy, Amanda ;

You, Y. Nancy .

JAMA SURGERY, 2017, 152 (11) :1086-1088

[8] Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases [J].

Connor, Ashton A. ;

Denroche, Robert E. ;

Jang, Gun Ho ;

Lemire, Mathieu ;

Zhang, Amy ;

Chan-Seng-Yue, Michelle ;

Wilson, Gavin ;

Grant, Robert C. ;

Merico, Daniele ;

Lungu, Ilinca ;

Bartlett, John M. S. ;

Chadwick, Dianne ;

Liang, Sheng-Ben ;

Eagles, Jenna ;

Mbabaali, Faridah ;

Miller, Jessica K. ;

Krzyzanowski, Paul ;

Armstrong, Heather ;

Luo, Xuemei ;

Jorgensen, Lars G. T. ;

Romero, Joan M. ;

Bavi, Prashant ;

Fischer, Sandra E. ;

Serra, Stefano ;

Hafezi-Bakhtiari, Sara ;

Caglar, Derin ;

Roehrl, Michael H. A. ;

Cleary, Sean ;

Hollingsworth, Michael A. ;

Petersen, Gloria M. ;

Thayer, Sarah ;

Law, Calvin H. L. ;

Nanji, Sulaiman ;

Golan, Talia ;

Smith, Alyssa L. ;

Borgida, Ayelet ;

Dodd, Anna ;

Hedley, David ;

Wouters, Bradly G. ;

O'Kane, Grainne M. ;

Wilson, Julie M. ;

Zogopoulos, George ;

Notta, Faiyaz ;

Knox, Jennifer J. ;

Gallinger, Steven .

CANCER CELL, 2019, 35 (02) :267-+

[9] Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma [J].

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 ;

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 .

JAMA ONCOLOGY, 2017, 3 (06) :774-783

[10] FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer [J].

Conroy, T. ;

Hammel, P. ;

Hebbar, M. ;

Ben Abdelghani, M. ;

Wei, A. C. ;

Raoul, J. -L. ;

Chone, L. ;

Francois, E. ;

Artru, P. ;

Biagi, J. J. ;

Lecomte, T. ;

Assenat, E. ;

Faroux, R. ;

Ychou, M. ;

Volet, J. ;

Sauvanet, A. ;

Breysacher, G. ;

Di Fiore, F. ;

Cripps, C. ;

Kavan, P. ;

Texereau, P. ;

Bouhier-Leporrier, K. ;

Khemissa-Akouz, F. ;

Legoux, J. -L. ;

Juzyna, B. ;

Gourgou, S. ;

O'Callaghan, C. J. ;

Jouffroy-Zeller, C. ;

Rat, P. ;

Malka, D. ;

Castan, F. ;

Bachet, J. -B. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 379 (25) :2395-2406

← 1 2 3 4 5 6 →