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Characterizing Driver Gene Heterogen...

Fischer, Catherine G.

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Characterizing Driver Gene Heterogeneity and Clonal Origin of Intraductal Papillary Mucinous Neoplasms of The Pancreas.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Characterizing Driver Gene Heterogeneity and Clonal Origin of Intraductal Papillary Mucinous Neoplasms of The Pancreas./
Author:	Fischer, Catherine G.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	95 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
Contained By:	Dissertations Abstracts International81-08B.
Subject:	Biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27726299
ISBN:	9781392433294

Characterizing Driver Gene Heterogeneity and Clonal Origin of Intraductal Papillary Mucinous Neoplasms of The Pancreas.
Fischer, Catherine G.

Characterizing Driver Gene Heterogeneity and Clonal Origin of Intraductal Papillary Mucinous Neoplasms of The Pancreas. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 95 p.

Source: Dissertations Abstracts International, Volume: 81-08, Section: B.

Thesis (Ph.D.)--The Johns Hopkins University, 2019.

This item must not be sold to any third party vendors.

Intraductal papillary mucinous neoplasms (IPMNs) are precancerous lesions that can progress to invasive pancreatic cancer and a key system in which to study early pancreatic tumorigenesis. We used a combination of multi-region and single-cell targeted next generation sequencing to assess the diversity of somatic driver gene mutations in IPMNs. The resulting data, combined with evolutionary modeling, whole exome sequencing, and in situ mutation detection, show that the earliest stages of pancreatic tumorigenesis are characterized by independent clones with distinct early driver gene mutations, thus revealing the polyclonal origin of precancerous pancreatic neoplasms. In addition, multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Collectively, our data demonstrate substantial genetic heterogeneity within IPMN, predominately in IPMNs with low-grade dysplasia. These data also challenge traditional monoclonal tumor origin models and transform our understanding of the evolutionary history of pancreatic neoplasia. Understanding the mechanism underlying polyclonal precancers may reveal new strategies to identify patients at increased risk of developing invasive pancreatic cancer.

ISBN: 9781392433294Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Pancreas

Characterizing Driver Gene Heterogeneity and Clonal Origin of Intraductal Papillary Mucinous Neoplasms of The Pancreas.
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520 $a Intraductal papillary mucinous neoplasms (IPMNs) are precancerous lesions that can progress to invasive pancreatic cancer and a key system in which to study early pancreatic tumorigenesis. We used a combination of multi-region and single-cell targeted next generation sequencing to assess the diversity of somatic driver gene mutations in IPMNs. The resulting data, combined with evolutionary modeling, whole exome sequencing, and in situ mutation detection, show that the earliest stages of pancreatic tumorigenesis are characterized by independent clones with distinct early driver gene mutations, thus revealing the polyclonal origin of precancerous pancreatic neoplasms. In addition, multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Collectively, our data demonstrate substantial genetic heterogeneity within IPMN, predominately in IPMNs with low-grade dysplasia. These data also challenge traditional monoclonal tumor origin models and transform our understanding of the evolutionary history of pancreatic neoplasia. Understanding the mechanism underlying polyclonal precancers may reveal new strategies to identify patients at increased risk of developing invasive pancreatic cancer.
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