TY - JOUR
T1 - Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions
AU - Kuboki, Yuko
AU - Fischer, Catherine G.
AU - Beleva Guthrie, Violeta
AU - Huang, Wenjie
AU - Yu, Jun
AU - Chianchiano, Peter
AU - Hosoda, Waki
AU - Zhang, Hao
AU - Zheng, Lily
AU - Shao, Xiaoshan
AU - Thompson, Elizabeth D.
AU - Waters, Kevin
AU - Poling, Justin
AU - He, Jin
AU - Weiss, Matthew J.
AU - Wolfgang, Christopher L.
AU - Goggins, Michael G.
AU - Hruban, Ralph H.
AU - Roberts, Nicholas J.
AU - Karchin, Rachel
AU - Wood, Laura D.
N1 - Publisher Copyright:
Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2019/3
Y1 - 2019/3
N2 - Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next-generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. 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. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions.
AB - Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next-generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. 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. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions.
KW - genetic heterogeneity
KW - intraductal papillary mucinous neoplasm
KW - pancreatic cancer precursor lesion
KW - single-cell sequencing
KW - somatic mutation
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U2 - 10.1002/path.5194
DO - 10.1002/path.5194
M3 - Article
C2 - 30430578
AN - SCOPUS:85060146445
SN - 0022-3417
VL - 247
SP - 347
EP - 356
JO - Journal of Pathology
JF - Journal of Pathology
IS - 3
ER -