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Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers
Open accessAbstract
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.
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Γκουντάκος, Α., Singhi, A. D., Westphalen, C. B., Scarpa, A., & Luchini, C. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.01.009 · Cited by 36
“…coexistence of fusion genes with another actionable alteration [76] [e.g., a case with FGFR2 fusion and microsatellite instability (MSI)] [23]; and (iii) the possible role of pancreas-specific cell of origin or tissue microenvironment (desmoplastic stroma, immune cells) in influencing…”
Self-citationMoving the Needle on Precision Medicine in Pancreatic Cancer
O'Kane, G. M., & Lowery, M. A. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02514 · Cited by 34
Cheng, K., Li, X., Lv, W., Zhao, G., Zhou, R., Chen, C., Yang, H., Li, R., Li, Z., Chen, Y., et al. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02031-8 · Cited by 34
From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer
Bazzichetto, C., Conciatori, F., Luchini, C., Simionato, F., Santoro, R., Vaccaro, V., Corbo, V., Falcone, I., Ferretti, G., Cognetti, F., et al. (2020) · Cells · doi:10.3390/cells9020309 · Cited by 32
“In terms of targeted therapy, the BRAF (v-raf murine sarcoma viral oncogene homolog B1) oncogene may also be mutated in PC, but its prevalence is less than 2% of all cases [50].”
BackgroundInfluentialFusco, M. J., Saeed‐Vafa, D., Carballido, E. M., Boyle, T. A., Malafa, M. P., Blue, K., Teer, J. K., Walko, C. M., McLeod, H. L., Hicks, J. K., et al. (2021) · JCO Precision Oncology · doi:10.1200/po.20.00265 · Cited by 34
Ambrosini, M., Re, M. D., Manca, P., Hendifar, A. E., Drilon, A. E. D. C., Harada, G., Ree, A. H., Klempner, S. J., Mælandsmo, G. M., Flatmark, K., et al. (2022) · JCO Precision Oncology · doi:10.1200/po.22.00015 · Cited by 34
“Regarding pancreatic cancer, available data show that potentially actionable alterations, such as BRAF mutations and FGFR2-3, NTRK, RET, MET and ALK fusions, are restricted to KRAS wild-type tumors, suggesting their role as cancer drivers.(19,20) Recently, various studies have evaluated the activity of new selective i…”
BackgroundSelf-citationClinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer
Umemoto, K., Sunakawa, Y., Ueno, M., Furukawa, M., Mizuno, N., Sudo, K., Kawamoto, Y., Kajiwara, T., Ohtsubo, K., Okano, N., et al. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02189-y · Cited by 35
Malignant epithelial/exocrine tumors of the pancreas
Luchini, C., Grillo, F., Fassan, M., Vanoli, A., Capelli, P., Paolino, G., Ingravallo, G., Renzulli, G., Doglioni, C., D’Amuri, A., et al. (2020) · Pathologica · doi:10.32074/1591-951x-167 · Cited by 32
Precision medicine for KRAS wild-type pancreatic adenocarcinomas
Ben-Ammar, I., Rousseau, A., Nicolle, R., Tarabay, A., Boige, V., Valéry, M., Pudlarz, T., Malka, D., Gelli, M., Fernandez-De-Sevilla, E., et al. (2023) · European Journal of Cancer · doi:10.1016/j.ejca.2023.113497 · Cited by 31
Rozengurt, E., & Eibl, G. (2021) · Cancers · doi:10.3390/cancers13205126 · Cited by 31
“Furthermore, a small number (3%) of PDAC patients harbor oncogenic activation of the RAF serine/threonine kinase B-RAF [15,16].”
BackgroundInfluentialATM Serine/Threonine Kinase and its Role in Pancreatic Risk
Nanda, N., & Roberts, N. J. (2020) · Genes · doi:10.3390/genes11010108 · Cited by 30
“Interestingly, the number of pathogenic germline ATM variants identified in male patients was greater than the number in female patients, and this difference was statistically significant [34].”
BackgroundSugimoto, M., Irie, H., Takagi, T. J., Suzuki, R., Konno, N., Asama, H., Sato, Y., Nakamura, J., Takasumi, M., Hashimoto, M., et al. (2020) · BMC Cancer · doi:10.1186/s12885-020-07588-5 · Cited by 29
Tarasiuk, A., Mackiewicz, T., Malecka-Panas, E. I., & Fichna, J. (2021) · Cancer Biology & Therapy · doi:10.1080/15384047.2021.1941584 · Cited by 29
Hendifar, A. E., Blais, E. M., Wolpin, B. M., Subbiah, V., Collisson, E. A., Singh, I., Cannon, T. L., Shaw, K. R. M., Petricoin, E. F., Klempner, S. J., et al. (2021) · JCO Precision Oncology · doi:10.1200/po.20.00494 · Cited by 31
“2 lines 17/81 (21) 15/52 (29) 1/16 (6) 14/36 (39)”
Self-citationUmemoto, K., Yamamoto, H., Oikawa, R., Takeda, H., Doi, A., Horie, Y., Arai, H., Ogura, T., Mizukami, T., Izawa, N., et al. (2022) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djac106 · Cited by 27
Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma
Huffman, B. M., Ellis, H., Jordan, A. C., Freed-Pastor, W. A., Perez, K. J., Rubinson, D. A., Sethi, N. S., Singh, H., Surana, R., Wolpin, B. M., et al. (2022) · Cancers · doi:10.3390/cancers14246223 · Cited by 31
“distribution of KRAS mutations: G12D (41%), G12V (31%), G12R (14%), Q61H (4%), and G12C (<1%) [27,30].”
BackgroundClinical and genomic characterisation of early-onset pancreatic cancer
Castet, F., Fabregat-Franco, C., Castillo, G., Navarro, V., Sierra, A., Acosta, D. A., López-Valbuena, D., Dienstmann, R., Tabernero, J. M., Vivancos, A. P., et al. (2023) · European Journal of Cancer · doi:10.1016/j.ejca.2023.113338 · Cited by 30
The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment
Sun, H., Zhang, B., & Li, H. (2020) · Technology in Cancer Research & Treatment · doi:10.1177/1533033820920969 · Cited by 28
Lee, M. S., & Pant, S. (2021) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_321255 · Cited by 30
Targeting KRAS in Pancreatic Cancer
Cowzer, D., Zameer, M., Conroy, M. R., Kölch, W., & Duffy, A. G. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12111870 · Cited by 34
Bansod, S., Dodhiawala, P. B., & Lim, K. (2021) · Cancers · doi:10.3390/cancers13215481 · Cited by 28
“8%) of PDAC cases possess microsatellite instability or high mutational burden which render them potentially responsive to checkpoint immunotherapy [4,5].”
BackgroundAre targeted therapies or immunotherapies effective in metastatic pancreatic adenocarcinoma?
Rémond, M., Pellat, A., Brézault, C., Dhooge, M., & Coriat, R. (2022) · ESMO Open · doi:10.1016/j.esmoop.2022.100638 · Cited by 28
Immunosuppressive tumor microenvironment in pancreatic cancer: mechanisms and therapeutic targets
Pan, D., Li, X., Qiao, X., & Wang, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1582305 · Cited by 31
Targeting DNA Damage Repair Mechanisms in Pancreas Cancer
Perkhofer, L., Golan, T., Cuyle, P.-J. A., Matysiak‐Budnik, T., Laethem, J. V., Macarulla, T. M., Cauchin, E., Kleger, A., Beutel, A. K., Gout, J., et al. (2021) · Cancers · doi:10.3390/cancers13174259 · Cited by 25
Self-citationZhan, Q., Wen, C., Zhao, Y., Fang, L., Jin, Y., Zhang, Z., Zou, S., Li, F., Yang, Y., Wu, L., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103716 · Cited by 25
“This study enrolled a Chinese cohort consisting of 608 patients pathologically diagnosed with PAAD from a commercial genetic testing database (Genecast Connect) and Ruijin Hospital (Shanghai, China) between March 2018 and April 2020.”
BackgroundResultInfluentialBRAF-Driven Pancreatic Cancer: Prevalence, Molecular Features, and Therapeutic Opportunities
Ciner, A., Jiang, Y., & Hausner, P. F. (2022) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-22-0626 · Cited by 25
Semaan, A., Bernard, V., Lee, J. J., Wong, J., Huang, J. H., Swartzlander, D. B., Stephens, B. M., Monberg, M. E., Weston, B. R., Bhutani, M. S., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2667 · Cited by 25
“These results match prevalent actionable mutations previously reported in 17% to 48% of PDAC cases (19, 20, 22).”
ResultSelf-citationAnimal Models of Cancer-Related Pain: Current Perspectives in Translation
Pineda-Farías, J. B., Saloman, J. L., & Scheff, N. N. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.610894 · Cited by 24
Roles of the nervous system in pancreatic cancer
Wakiya, T., Ishido, K., Yoshizawa, T., Kanda, T., & Hakamada, K. (2021) · Annals of Gastroenterological Surgery · doi:10.1002/ags3.12459 · Cited by 22
Age and prognosis in patients with pancreatic cancer: a population-based study
van Dongen, J. C., van der Geest, L. G., de Meijer, V. E., van Santvoort, H. C., de Vos‐Geelen, J., Besselink, M. G., Koerkamp, B. G., Wilmink, J. W., van Eijck, C. H. J., & on behalf of the Dutch Pancreatic Cancer Group (2021) · Acta Oncologica · doi:10.1080/0284186x.2021.2016949 · Cited by 24
KRAS as a Key Oncogene in the Clinical Precision Diagnosis and Treatment of Pancreatic Cancer
Dai, M., Chen, S., Teng, X., Chen, K., & Cheng, W. (2022) · Journal of Cancer · doi:10.7150/jca.76695 · Cited by 28
“Subsequent studies confirmed these findings and identified four major driver mutations including KRAS, tumor protein p53 (TP53), SMAD family member 4 (SMAD4) and cyclin dependent kinase inhibitor 2A (CDKN2A) [5], among which, KRAS mutation is the most common one, with a mutation rate up to 90%.”
BackgroundCa2+ Signaling and Its Potential Targeting in Pancreatic Ductal Carcinoma
Bettaieb, L., Brulé, M., Chomy, A., Diedro, M., Fruit, M., Happernegg, E., Heni, L., Horochowska, A., Housseini, M., Klouyovo, K., et al. (2021) · Cancers · doi:10.3390/cancers13123085 · Cited by 24
“Finally, kinase inhibitors have been shown to be effective against PDAC with the kinase resulting from the gene fusion [45].”
BackgroundKimura, H., Paranal, R. M., Nanda, N., Wood, L. D., Eshleman, J. R., Hruban, R. H., Goggins, M. G., Klein, A. P., The Familial Pancreatic Cancer Genome Sequencing Project, & Roberts, N. J. (2022) · eLife · doi:10.7554/elife.71137 · Cited by 23
Exceptional Response to Erdafitinib in FGFR2-Mutated Metastatic Pancreatic Ductal Adenocarcinoma
Ng, C., Glaspy, J. A., Placencio-Hickok, V., Thomassian, S., Gong, J., Osipov, A., Hendifar, A. E., & Moshayedi, N. (2022) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2022.7039 · Cited by 23
Self-citationAdherence to NCCN Genetic Testing Guidelines in Pancreatic Cancer and Impact on Treatment
Crowley, F., Gandhi, S., Rudshteyn, M., Sehmbhi, M., & Cohen, D. J. (2023) · The Oncologist · doi:10.1093/oncolo/oyad044 · Cited by 23
Sakakida, T., Ishikawa, T., Doi, T., Morita, R., Kataoka, S., Miyake, H., Yamaguchi, K., Moriguchi, M., Sogame, Y., Yasuda, H., et al. (2023) · Journal of Gastroenterology · doi:10.1007/s00535-023-02058-8 · Cited by 23
“We also found that potentially targetable genes, such as KMT2D , one of the genes of the KMT2 family, and ARID1A , were more common in the presence of MSI-H/ TMB-high, being consistent with previous reports [27, 37].”
Resection of Recurrent Pancreatic Cancer: Who Can Benefit?
Nienhüser, H., Büchler, M. W., & Schneider, M. A. (2021) · Visceral Medicine · doi:10.1159/000519754 · Cited by 22
Ashida, R., & Kitano, M. (2022) · Digestive Endoscopy · doi:10.1111/den.14344 · Cited by 23
Gleeson, F. C., Levy, M. J., Jackson, R. A., Murphy, S. J., Halling, K. C., Kipp, B. R., Graham, R. P., & Zhang, L. (2019) · Pancreatology · doi:10.1016/j.pan.2019.12.002 · Cited by 21
Intraductal Pancreatic Mucinous Neoplasms: A Tumor-Biology Based Approach for Risk Stratification
Nasca, V., Chiaravalli, M., Piro, G., Esposito, A., Salvatore, L., Tortora, G., Corbo, V., & Carbone, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176386 · Cited by 21
“GNAS mutations are found in around 70% of IPMNs and are absent in other precursor lesions or in invasive PDAC not associated to IPMN [66,74,75].”
BackgroundPoly( ADP ‐ribose) polymerase inhibition in pancreatic cancer
Singh, H. M., Bailey, P. J., Hübschmann, D., Berger, A. K., Neoptolemos, J. P., Jäger, D., Siveke, J. T., & Springfeld, C. (2020) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22932 · Cited by 22
First international workshop of the ATM and cancer risk group (4-5 December 2019)
Lesueur, F., Easton, D. F., Renault, A., Tavtigian, S. V., Bernstein, J. L., Kote‐Jarai, Z., Eeles, R. A., Plaseska-Karanfia, D., Feliubadaló, L., Spanish ATM working group, et al. (2021) · Familial Cancer · doi:10.1007/s10689-021-00248-y · Cited by 21
Immunotherapy and Pancreatic Cancer: A Lost Challenge?
Laface, C., Memeo, R., Maselli, F. M., Santoro, A. N., Iaia, M. L., Ambrogio, F., Laterza, M., Cazzato, G., Guarini, C., Santis, P. D., et al. (2023) · Life · doi:10.3390/life13071482 · Cited by 22
Gower, A., Golestany, B., Gong, J., Singhi, A. D., & Hendifar, A. E. (2020) · JCO Precision Oncology · doi:10.1200/po.19.00365 · Cited by 23
“38%ofKRASwild-type tumors have genomic alterations that could activate theMAPK signaling cascade.(9) Identification of molecular alterations in patients with KRAS wild-type status that may drive oncogenesis will help guide therapeutic intervention in a small but clinically relevant population.”
BackgroundSelf-citationBiological Hallmarks and New Therapeutic Approaches for the Treatment of PDAC
Digiacomo, G., Volta, F., Garajová, I., Balsano, R., & Cavazzoni, A. (2021) · Life · doi:10.3390/life11080843 · Cited by 21
Advancements in Systemic Therapy for Pancreatic Cancer
Brown, T. J., Reiss, K. A., & O’Hara, M. H. (2023) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_397082 · Cited by 21
Metadata
- Authors
- Singhi, A. D., George, B., Greenbowe, J. R., Chung, J., Suh, J., Maitra, A., Klempner, S. J., Hendifar, A., Milind, J. M., Golan, T., Brand, R. E., Zureikat, A. H., Roy, S., Schrock, A. B., Miller, V. A., Ross, J. S., Ali, S. M., & Bahary, N.
- Affiliations
- University of Pittsburgh Medical Center (US)
- Medical College of Wisconsin (US)
- Foundation Medicine (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- Cedars-Sinai Medical Center (US)
- Tel Aviv University (IL)
- Corresponding author
- Singhi, Aatur D.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 156
- Issue
- 8
- Pages
- 2242-2253.e4
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2919944461
- Cited by
- 348
- References
- 60
- Citations by year
- 2026: 27 · 2025: 43 · 2024: 51 · 2023: 55 · 2022: 56 · 2021: 63 · 2020: 43 · 2019: 9
- FWCI
- 17.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Gastroenterology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Pancreatic Cancer Action Network
- Association for Molecular Pathology
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- pancreatic ductal adenocarcinoma, actionable genomic alterations, KRAS mutation, TP53, CDKN2A, SMAD4, MAPK signaling, gene fusion, gene amplification, microsatellite instability, tumor mutational burden, DNA repair, intraductal papillary mucinous neoplasm, biomarkers, therapeutic target
- MeSH terms
- Fibroblast Growth Factor-23, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Adenocarcinoma, Mucinous, Chromosome Mapping, Female, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Pancreatic Neoplasms, Retrospective Studies, Biomarkers, Tumor, Genetic Variation, Cohort Studies, Gene Expression Regulation, Neoplastic, Carcinoma, Pancreatic Ductal, Young Adult, Genomic Structural Variation, Molecular Targeted Therapy, Real-Time Polymerase Chain Reaction
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