Molecular Alterations Associated with DNA Repair in Pancreatic Adenocarcinoma Are Associated with Sites of Recurrence

Margaret D. Ferguson, Lei Dong, Jim Wan, Jeremiah Deneve, Paxton V. Dickson, Stephen W. Behrman, David Shibata, Michael Martin, Evan Glazer

Research output: Contribution to journalArticle

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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations—gene mutations, variations in copy number, and changes in gene expression—has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. Methods: Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student’s t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson’s χ 2 . Results: Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62%, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72%) than in other sites (59%, p = 0.042). Low expression of ERCC1 was found in 49% of lung metastases from PDAC but only 15% in PDAC in the pancreas (p < 0.001). Five of the 8 molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p < 0.001). Conclusions: Aberrant expression or mutation in genes involved in DNA maintenance is found in association with specific sites of metastatic PDAC. Personalizing therapy for metastatic PDAC based on site of disease and their associated molecular alterations warrants further investigation.

Original languageEnglish (US)
Pages (from-to)285-291
Number of pages7
JournalJournal of Gastrointestinal Cancer
Volume50
Issue number2
DOIs
StatePublished - Jun 15 2019

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DNA Repair
Adenocarcinoma
Recurrence
Mutation
Neoplasm Metastasis
Lung
Pancreas
Maintenance
Peritoneum
Genes
Neoplasms
Analysis of Variance
Databases
Students
Liver
DNA
Incidence
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Gastroenterology

Cite this

Molecular Alterations Associated with DNA Repair in Pancreatic Adenocarcinoma Are Associated with Sites of Recurrence. / Ferguson, Margaret D.; Dong, Lei; Wan, Jim; Deneve, Jeremiah; Dickson, Paxton V.; Behrman, Stephen W.; Shibata, David; Martin, Michael; Glazer, Evan.

In: Journal of Gastrointestinal Cancer, Vol. 50, No. 2, 15.06.2019, p. 285-291.

Research output: Contribution to journalArticle

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abstract = "Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations—gene mutations, variations in copy number, and changes in gene expression—has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. Methods: Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student’s t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson’s χ 2 . Results: Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62{\%}, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72{\%}) than in other sites (59{\%}, p = 0.042). Low expression of ERCC1 was found in 49{\%} of lung metastases from PDAC but only 15{\%} in PDAC in the pancreas (p < 0.001). Five of the 8 molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p < 0.001). Conclusions: Aberrant expression or mutation in genes involved in DNA maintenance is found in association with specific sites of metastatic PDAC. Personalizing therapy for metastatic PDAC based on site of disease and their associated molecular alterations warrants further investigation.",
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AU - Ferguson, Margaret D.

AU - Dong, Lei

AU - Wan, Jim

AU - Deneve, Jeremiah

AU - Dickson, Paxton V.

AU - Behrman, Stephen W.

AU - Shibata, David

AU - Martin, Michael

AU - Glazer, Evan

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N2 - Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations—gene mutations, variations in copy number, and changes in gene expression—has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. Methods: Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student’s t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson’s χ 2 . Results: Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62%, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72%) than in other sites (59%, p = 0.042). Low expression of ERCC1 was found in 49% of lung metastases from PDAC but only 15% in PDAC in the pancreas (p < 0.001). Five of the 8 molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p < 0.001). Conclusions: Aberrant expression or mutation in genes involved in DNA maintenance is found in association with specific sites of metastatic PDAC. Personalizing therapy for metastatic PDAC based on site of disease and their associated molecular alterations warrants further investigation.

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