J Pathol Transl Med.  2021 May;55(3):192-201. 10.4132/jptm.2021.01.23.

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

• Kumari N
• Singh RK
• Mishra SK
• Krishnani N
• Mohindra S
• L. R

• KMID: 2515924
• DOI: http://doi.org/10.4132/jptm.2021.01.23

Abstract

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.

Keyword

Ampullary; Exome; Intestinal; Pancreatobiliary

Figure

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  Fig. 1 Microphotograph of intestinal differentiation. Low-power (A) and high-power (B) views showing tall columnar cells with elongated to oblong basal nuclei and nuclear stratification.

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  Fig. 2 Microphotograph of pancreatobiliary differentiation. Low-power (A) and high-power (B) views showing cuboidal to low columnar cells with rounded centrally placed nuclei with no nuclear stratification. Desmoplastic stroma can be observed between the tumor glands.

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  Fig. 3 Immunohistochemical stains (A, CDX2; B, cytokeratin 20; C, MUC2) expressed in the intestinal type of ampullary cancer.

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  Fig. 4 Immunohistochemical stains (A, MUC1; B, cytokeratin [CK] 17; C, CK7) expressed in the pancreatobiliary type of ampullary cancer.

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  Fig. 5 Schema representing the workflow for whole-exome sequencing and data analysis. UTR, untranslated region.

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  Fig. 6 (A) Deleterious somatic variants in intestinal (INT) ampullary cancers. (B) Deleterious somatic variants in pancreatobiliary (PB) ampullary cancers.

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  Fig. 7 (A) Genes forming part of the cellular component in intestinal and pancreatobiliary types of ampullary carcinoma. (B) Genes responsible for different classes of proteins in intestinal and pancreatobiliary types of ampullary carcinoma. (C) Genes involved in different biological functions and processes in intestinal and pancreatobiliary types of ampullary carcinoma.

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  Fig. 8 Pathways involving the significantly most frequently mutated genes in intestinal and pancreatobiliary subtypes of ampullary carcinoma (p < .002).

Reference

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