Identification of PI3K-AKT signaling as the dominant altered pathway in intestinal type ampullary cancers through whole-exome sequencing

Niraj Kumari; Rajneesh K. Singh; Shravan K. Mishra; Narendra Krishnani; Samir Mohindra; Raghvendra L.

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저자정보: Niraj Kumari (Sanjay Gandhi Postgraduate Institute of Medical Sciences) Rajneesh K. Singh (Sanjay Gandhi Postgraduate Institute of Medical Sciences) Shravan K. Mishra (Sanjay Gandhi Postgraduate Institute of Medical Sciences) Narendra Krishnani (Sanjay Gandhi Postgraduate Institute of Medical Sciences) Samir Mohindra (Sanjay Gandhi Postgraduate Institute of Medical Sciences) Raghvendra L. (All India Institute of Medical Sciences)

저널정보: 대한병리학회 Journal of Pathology and Translational Medicine Journal of Pathology and Translational Medicine 제55권 제3호

발행연도: 2021.1

수록면: 192 - 201 (10page)

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Background: The genetic landscape of intestinal (INT) and pancreatobiliary (PB) type ampullary cancer (AC) has been evolving with distinct as well as overlapping molecular profiles. Methods: We performed whole-exome sequencing in 37 cases of AC to identify the targetable molecular profiles of INT and PB tumors. Paired tumor-normal sequencing was performed on the HiSeq 2500 Illumina platform. Results: There were 22 INT, 13 PB, and two cases of mixed differentiation of AC that exhibited a total of 1,263 somatic variants in 112 genes (2?257 variants/case) with 183 somatic deleterious variants. INT showed variations in 78 genes (1?31/case), while PB showed variations in 51 genes (1?29/case). Targetable mutations involving one or more major pathways were found in 86.5% of all ACs. Mutations in APC, CTNNB1, SMAD4, KMT2, EPHA, ERBB, and Notch genes were more frequent in INT tumors, while chromatin remodeling complex mutations were frequent in PB tumors. In the major signaling pathways, the phosphoinositide 3-kinase (PI3)/AKT and RAS/mitogen-activated protein kinase (MAPK) pathways were significantly mutated in 70% of cases (82% INT, 46% PB, p = .023), with PI3/AKT mutation being more frequent in INT and RAS/MAPK in PB tumors. Tumor mutation burden was low in both differentiation types, with 1.6/Mb in INT and 0.8/Mb in PB types (p = .217). Conclusions: The exome data suggest that INT types are genetically more unstable than PB and involve mutations in tumor suppressors, oncogenes, transcription factors, and chromatin remodeling genes. The spectra of the genetic profiles of INT and PB types suggested primary targeting of PI3/AKT in INT and RAS/RAF and PI3/AKT pathways in PB carcinomas.

#Ampullary #Exome #Intestinal #Pancreatobiliary

참고문헌 (17)

참고문헌 신청

Adsay V / 2012 / Ampullary region carcinomas : definition and site specific classification with delineation of four clinicopathologically and prognostically distinct subsets in an analysis of 249 cases / Am J Surg Pathol 36:1592~1608

Benhamiche AM / 2000 / Cancer of the ampulla of Vater : results of a 20-year populationbased study / Eur J Gastroenterol Hepatol 12:75~79

Demeure MJ / 2012 / Cancer of the ampulla of Vater : analysis of the whole genome sequence exposes a potential therapeutic vulnerability / Genome Med 4:56

Kim WS / 2012 / Clinical significance of pathologic subtype in curatively resected ampulla of vater cancer / J Surg Oncol 105:266~272

Colussi O / 2015 / Prognostic score for recurrence after Whipple's pancreaticoduodenectomy for ampullary carcinomas;results of an AGEO retrospective multicenter cohort / Eur J Surg Oncol 41:520~526

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