Aatur D Singhi1, Ben George2, Joel R Greenbowe3, Jon Chung3, James Suh3, Anirban Maitra4, Samuel J Klempner5, Andrew Hendifar6, Javle M Milind4, Talia Golan7, Randall E Brand8, Amer H Zureikat9, Somak Roy10, Alexa B Schrock3, Vincent A Miller3, Jeffrey S Ross3, Siraj M Ali3, Nathan Bahary8. 1. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: singhiad@upmc.edu. 2. Department of Medicine, Division of Medical Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin. 3. Foundation Medicine, Inc, Cambridge, Massachusetts. 4. Sheikh Ahmed Pancreatic Cancer Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. 5. The Angeles Clinic and Research Institute, Los Angeles, California; Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California. 6. Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California. 7. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 8. Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 9. Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 10. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Abstract
BACKGROUND & AIMS: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations. METHODS: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci. RESULTS: KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs. CONCLUSIONS: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.
BACKGROUND & AIMS: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations. METHODS: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci. RESULTS:KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs. CONCLUSIONS: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.
Authors: Mark E Lowe; Dana K Andersen; Richard M Caprioli; Jyoti Choudhary; Zobeida Cruz-Monserrate; Anil K Dasyam; Christopher E Forsmark; Fred S Gorelick; Joe W Gray; Mark Haupt; Kimberly A Kelly; Kenneth P Olive; Sylvia K Plevritis; Noa Rappaport; Holger R Roth; Hanno Steen; S Joshua Swamidass; Temel Tirkes; Aliye Uc; Kirill Veselkov; David C Whitcomb; Aida Habtezion Journal: Pancreas Date: 2019 Nov/Dec Impact factor: 3.327
Authors: Michael J Fusco; Daryoush Saeed-Vafa; Estrella M Carballido; Theresa A Boyle; Mokenge Malafa; Kirsten L Blue; Jamie K Teer; Christine M Walko; Howard L McLeod; J Kevin Hicks; Martine Extermann; Jason B Fleming; Todd C Knepper; Dae Won Kim Journal: JCO Precis Oncol Date: 2021-01-11
Authors: Fabienne Lesueur; Douglas F Easton; Anne-Laure Renault; Sean V Tavtigian; Jonine L Bernstein; Zsofia Kote-Jarai; Rosalind A Eeles; Dijana Plaseska-Karanfia; Lidia Feliubadaló; Banu Arun; Natalie Herold; Beatrix Versmold; Rita Katharina Schmutzler; Tú Nguyen-Dumont; Melissa C Southey; Leila Dorling; Alison M Dunning; Paola Ghiorzo; Bruna Samia Dalmasso; Eve Cavaciuti; Dorothée Le Gal; Nicholas J Roberts; Mev Dominguez-Valentin; Matti Rookus; Alexander M R Taylor; Alisa M Goldstein; David E Goldgar; Dominique Stoppa-Lyonnet; Nadine Andrieu Journal: Fam Cancer Date: 2021-06-14 Impact factor: 2.375