Whole-exome sequencing of pancreatic neoplasms with acinar differentiation

Yuchen Jiao, Raluca Yonescu, G. Johan A Offerhaus, David S. Klimstra, Anirban Maitra, James R. Eshleman, James G. Herman, Weijie Poh, Lorraine Pelosof, Christopher L. Wolfgang, Bert Vogelstein, Kenneth W. Kinzler, Ralph H. Hruban, Nickolas Papadopoulos, Laura D. Wood

Research output: Contribution to journalArticle

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Abstract

Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.

Original languageEnglish (US)
Pages (from-to)428-435
Number of pages8
JournalJournal of Pathology
Volume232
Issue number4
DOIs
StatePublished - Mar 2014

Fingerprint

Exome
Pancreatic Neoplasms
Mutation
Acinar Cell Carcinoma
Neoplasms
Carcinoma
Genes
Multiple Endocrine Neoplasia Type 1
Loss of Heterozygosity
Fluorescence In Situ Hybridization
Base Pairing
Adenocarcinoma
Chromosomes
Pancreatic Carcinoma

Keywords

  • acinar cell carcinoma
  • carcinoma
  • genetics
  • pancreas
  • pancreatoblastoma
  • sequencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Jiao, Y., Yonescu, R., Offerhaus, G. J. A., Klimstra, D. S., Maitra, A., Eshleman, J. R., ... Wood, L. D. (2014). Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. Journal of Pathology, 232(4), 428-435. https://doi.org/10.1002/path.4310

Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. / Jiao, Yuchen; Yonescu, Raluca; Offerhaus, G. Johan A; Klimstra, David S.; Maitra, Anirban; Eshleman, James R.; Herman, James G.; Poh, Weijie; Pelosof, Lorraine; Wolfgang, Christopher L.; Vogelstein, Bert; Kinzler, Kenneth W.; Hruban, Ralph H.; Papadopoulos, Nickolas; Wood, Laura D.

In: Journal of Pathology, Vol. 232, No. 4, 03.2014, p. 428-435.

Research output: Contribution to journalArticle

Jiao, Y, Yonescu, R, Offerhaus, GJA, Klimstra, DS, Maitra, A, Eshleman, JR, Herman, JG, Poh, W, Pelosof, L, Wolfgang, CL, Vogelstein, B, Kinzler, KW, Hruban, RH, Papadopoulos, N & Wood, LD 2014, 'Whole-exome sequencing of pancreatic neoplasms with acinar differentiation', Journal of Pathology, vol. 232, no. 4, pp. 428-435. https://doi.org/10.1002/path.4310
Jiao Y, Yonescu R, Offerhaus GJA, Klimstra DS, Maitra A, Eshleman JR et al. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. Journal of Pathology. 2014 Mar;232(4):428-435. https://doi.org/10.1002/path.4310
Jiao, Yuchen ; Yonescu, Raluca ; Offerhaus, G. Johan A ; Klimstra, David S. ; Maitra, Anirban ; Eshleman, James R. ; Herman, James G. ; Poh, Weijie ; Pelosof, Lorraine ; Wolfgang, Christopher L. ; Vogelstein, Bert ; Kinzler, Kenneth W. ; Hruban, Ralph H. ; Papadopoulos, Nickolas ; Wood, Laura D. / Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. In: Journal of Pathology. 2014 ; Vol. 232, No. 4. pp. 428-435.
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