Abstract
BackgroundGastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis.ResultsBoth the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 (FGFR2) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 (TGFBR2), indicating the divergent in vivo evolution of a TGFBR2-mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1-/-; Tp53-/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo, confirming Tgfbr2 metastasis suppressor activity.ConclusionsWe document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0428-9) contains supplementary material, which is available to authorized users.
Highlights
Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality
Using the cBio the Cancer Genome Atlas Project (TCGA) portal [10], we identified a patient (TCGA-BR-6803) who had a similar complement of genetic aberrations in CDH1, TP53, and Fibroblast growth factor receptor 2 (FGFR2), all of which have been previously described in cancer as seen in the COSMIC cancer mutation repository
The metastasis had the same CDH1 and TP53 mutations as the primary tumor but lacked the FGFR2 amplification found in the primary cancer site (Figure 3c)
Summary
Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis. Studies of affected HDGC individuals’ tumors provide a unique opportunity to determine the essential drivers of diffuse gastric cancer in the context of CDH1 loss of function. A recent whole genome sequencing survey of diffuse gastric cancer identified frequent CDH1 mutations as the most common driver event [4]. Less is known about the identity and role of co-occurring drivers that contribute to diffuse gastric metastasis
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