By David Douglas
NEW YORK (Reuters Health) - 20/6/2019
Sequencing of whole exome and transcriptome of peritoneal carcinomatosis (PC) in patients with gastric adenocarcinoma (GAC) has given novel insights and opened up new therapeutic opportunities, according to Texas-based researchers.
As Dr. Jaffer A. Ajani told Reuters Health by email, "This is the first demonstration of the landscape of PC." And, he added, "We have identified many novel targets."
In a June 6 online paper in Gut, Dr. Ajani and colleagues at MD Anderson Cancer Center, Houston, note that PC is seen in as many as 45% of GAC patients and confers a poor prognosis.
To gain more information, the researchers performed whole-exome sequencing and whole transcriptome sequencing on 44 PC specimens from 43 patients.
There were shared genomic alterations between primary GACs and PCs but there were also distinct genomic alterations in PCs including an increased frequency of CDH1 and TAF1 mutations. Alterations associated with aggressive PC phenotypes, say the investigators, included increased mutations in TP53, CDH1, TAF1 and KMT2C, and higher level of "clock-like" mutational signature.
Among other findings in further analysis of grouped features were molecular subtypes dubbed "mesenchymal-like" and "epithelial-like". Compared to the epithelial subtypes, the mesenchymal-Iike subtype was associated with resistance to post-PC therapy (31% versus 71%). No such association was seen between the traditional histopathology-based subtypes and therapy response.
In addition, patients with the less responsive mesenchymal-like subtype showed high expression of immune checkpoint TIM-3, its ligand galectin-9, VISTA and transforming growth factor-beta, thus potentially providing therapeutic immune targets.
The researchers concede, "A limitation of our study is that we could not assess the corresponding primary GACs because all PC specimens were collected during a therapeutic procedure; collection of primary tumor was not clinically justifiable."
Nevertheless, they conclude, "Our results should widely stimulate analysis of many more patients with GAC with PC and doing so will lead to uncovering of enormous wealth of new knowledge to much better understand the biology of PC to develop more effective therapies through rational clinical trials."