Journal of Pathology and Translational Medicine

Original Articles

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.; J Pathol Transl Med. 2021;55(3):192-201. Published online March 9, 2021; DOI: https://doi.org/10.4132/jptm.2021.01.23

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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.

Citations

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Molecular pathways in periampullary cancer: An overview
Apurva, Real Sumayya Abdul Sattar, Asgar Ali, Nimisha, Abhay Kumar Sharma, Arun Kumar, Seneha Santoshi, Sundeep Singh Saluja
Cellular Signalling.2022; 100: 110461. CrossRef
Histologic subtyping of ampullary carcinoma for targeted therapy
Seung-Mo Hong
Journal of Pathology and Translational Medicine.2021; 55(3): 235. CrossRef

Expression of Cytokeratin 7 and 20 in Periampullary Carcinomas.: Jong Sun Choi, Na Rae Kim, Geung Hwan Ahn, Cheol Keun Park; Korean J Pathol. 2000;34(1):34-38.

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Abstract PDF: The distinction of carcinomas involving periampullary region is often difficult, even in the surgically resected specimens. To examine the differences in the expressions of cytokeratin (CK) 7 and 20 in the periampullary carcinomas, we performed immunohistochemical studies on surgically resected 20 pancreatic duct adenocarcinomas (PDA), 13 distal bile duct adenocarcinomas (DBA), 10 duodenal adenocarcinomas (DA), and 18 ampulla of Vater adenocarcinomas (AVA). We analyzed the relationships between CK 7/CK 20 immunoprofile, and tumor cell differentiation and tumor size. We interpreted diffuse cytoplasmic reactivity found in > or =5% of tumor cells as positive. In the majority of cases, PDA were CK 7 /20 (95%), DBA CK 7 /20 (92.3%), DA either CK 7 /20 (40%) or CK 7 /20 (30%), AVA either CK 7 /20 (50%) or CK 7 /20 (44.4%). In DA, there was an increased CK 20 negativity in less differentiated (moderately or poorly differentiated) cases (p<0.05) and in larger (> or =5 cm) tumor size (p=0.049). In AVA, there was a tendency of increased CK 20 positivity in less differentiated cases (p=0.10). In conclusion, the CK 7/CK 20 immunophenotype is useful in the differentiation of periampullary carcinomas: the CK 7 /CK 20 immunophenotype strongly suggests DA or AVA, whereas the CK 7 /CK 20 immunophenotype suggests PDA or DBA.

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