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One patient, two lesions, two oncogenic drivers of gastric cancer.

Alsinet C, Ranzani M, Adams DJ - Genome Biol. (2014)

Bottom Line: Deep-sequencing of a primary tumor and metastasis from a single patient, and functional validation in culture, reveals that TGFBR2 and FGFR2 act as drivers of gastric cancer.

View Article: PubMed Central - PubMed

ABSTRACT
Deep-sequencing of a primary tumor and metastasis from a single patient, and functional validation in culture, reveals that TGFBR2 and FGFR2 act as drivers of gastric cancer.

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Related in: MedlinePlus

Telling the story of a gastric cancer through sequencing and functional studies. (a) The primary gastric cancer clone carried CDH1 and TP53 mutations. After it had metastasized to the ovary, the primary gastric cancer acquired an amplification of the FGFR2 locus (black arrow). At this point, the primary tumor was removed by gastrectomy. Some three years later, the patient presented with abdominal masses. Sequencing of the metastatic tumor revealed loss of TGFBR2, but no amplification of FGFR2. Loss of TGFBR2 might have occurred after the clone had spread to the ovary (non-broken blue arrow) or alternatively might have occurred as the metastatic clone transited from the primary to the ovary (broken blue arrow). (b) A schematic representation of the functional validation of candidate oncogenic events. A human gastric cancer cell line harboring mutations in CDH1 and TP53, and an amplification of FGFR2, shows a significant reduction in survival in response to inhibition of the FGF pathway. Murine gastric organoids in which Tgfbr2 is suppressed by knockdown (kd) in the context of cdh1 and Tp53 loss undergo oncogenic transformation in vitro when grown subcutaneously (s.c.) in immunodeficient mice. The resultant tumor shows histology consistent with diffuse gastric cancer and undergoes metastatic spread to the lungs. Abbreviations: CDH1, cadherin-1; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; TGFBR2, TGF-beta receptor type-2; 3D, three-dimensional; TP53, cellular tumor antigen p53.
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Fig1: Telling the story of a gastric cancer through sequencing and functional studies. (a) The primary gastric cancer clone carried CDH1 and TP53 mutations. After it had metastasized to the ovary, the primary gastric cancer acquired an amplification of the FGFR2 locus (black arrow). At this point, the primary tumor was removed by gastrectomy. Some three years later, the patient presented with abdominal masses. Sequencing of the metastatic tumor revealed loss of TGFBR2, but no amplification of FGFR2. Loss of TGFBR2 might have occurred after the clone had spread to the ovary (non-broken blue arrow) or alternatively might have occurred as the metastatic clone transited from the primary to the ovary (broken blue arrow). (b) A schematic representation of the functional validation of candidate oncogenic events. A human gastric cancer cell line harboring mutations in CDH1 and TP53, and an amplification of FGFR2, shows a significant reduction in survival in response to inhibition of the FGF pathway. Murine gastric organoids in which Tgfbr2 is suppressed by knockdown (kd) in the context of cdh1 and Tp53 loss undergo oncogenic transformation in vitro when grown subcutaneously (s.c.) in immunodeficient mice. The resultant tumor shows histology consistent with diffuse gastric cancer and undergoes metastatic spread to the lungs. Abbreviations: CDH1, cadherin-1; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; TGFBR2, TGF-beta receptor type-2; 3D, three-dimensional; TP53, cellular tumor antigen p53.

Mentions: So what do the mutations identified in the tumors from this gastric cancer patient actually tell us (FigureĀ 1)? First, as a germline CDH1 mutation was found, it tells us that an early chapter in the story was loss of the wild-type allele of this gene, probably coinciding with biallelic loss of the TP53 gene (encoding cellular tumor antigen p53) or preceding it. Thus, mutation of CDH1 and TP53 are early events that probably drove tumor initiation and set the ball rolling. But why does the metastasis lack the FGFR2 amplification? This is most likely explained by the early dissemination of tumor cells from the primary lesion, which was removed by gastrectomy at presentation, to the metastatic site in the ovary, with these cells lying dormant, only to be reanimated years later by loss of TGFBR2. An alternative scenario could be that loss of TGFBR2 helped a cancer cell transit from the primary tumor to the metastatic site, where it lay in wait - either way, distal dissemination of the tumor must have been an early event occurring before removal of the primary.Figure 1


One patient, two lesions, two oncogenic drivers of gastric cancer.

Alsinet C, Ranzani M, Adams DJ - Genome Biol. (2014)

Telling the story of a gastric cancer through sequencing and functional studies. (a) The primary gastric cancer clone carried CDH1 and TP53 mutations. After it had metastasized to the ovary, the primary gastric cancer acquired an amplification of the FGFR2 locus (black arrow). At this point, the primary tumor was removed by gastrectomy. Some three years later, the patient presented with abdominal masses. Sequencing of the metastatic tumor revealed loss of TGFBR2, but no amplification of FGFR2. Loss of TGFBR2 might have occurred after the clone had spread to the ovary (non-broken blue arrow) or alternatively might have occurred as the metastatic clone transited from the primary to the ovary (broken blue arrow). (b) A schematic representation of the functional validation of candidate oncogenic events. A human gastric cancer cell line harboring mutations in CDH1 and TP53, and an amplification of FGFR2, shows a significant reduction in survival in response to inhibition of the FGF pathway. Murine gastric organoids in which Tgfbr2 is suppressed by knockdown (kd) in the context of cdh1 and Tp53 loss undergo oncogenic transformation in vitro when grown subcutaneously (s.c.) in immunodeficient mice. The resultant tumor shows histology consistent with diffuse gastric cancer and undergoes metastatic spread to the lungs. Abbreviations: CDH1, cadherin-1; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; TGFBR2, TGF-beta receptor type-2; 3D, three-dimensional; TP53, cellular tumor antigen p53.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4281955&req=5

Fig1: Telling the story of a gastric cancer through sequencing and functional studies. (a) The primary gastric cancer clone carried CDH1 and TP53 mutations. After it had metastasized to the ovary, the primary gastric cancer acquired an amplification of the FGFR2 locus (black arrow). At this point, the primary tumor was removed by gastrectomy. Some three years later, the patient presented with abdominal masses. Sequencing of the metastatic tumor revealed loss of TGFBR2, but no amplification of FGFR2. Loss of TGFBR2 might have occurred after the clone had spread to the ovary (non-broken blue arrow) or alternatively might have occurred as the metastatic clone transited from the primary to the ovary (broken blue arrow). (b) A schematic representation of the functional validation of candidate oncogenic events. A human gastric cancer cell line harboring mutations in CDH1 and TP53, and an amplification of FGFR2, shows a significant reduction in survival in response to inhibition of the FGF pathway. Murine gastric organoids in which Tgfbr2 is suppressed by knockdown (kd) in the context of cdh1 and Tp53 loss undergo oncogenic transformation in vitro when grown subcutaneously (s.c.) in immunodeficient mice. The resultant tumor shows histology consistent with diffuse gastric cancer and undergoes metastatic spread to the lungs. Abbreviations: CDH1, cadherin-1; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; TGFBR2, TGF-beta receptor type-2; 3D, three-dimensional; TP53, cellular tumor antigen p53.
Mentions: So what do the mutations identified in the tumors from this gastric cancer patient actually tell us (FigureĀ 1)? First, as a germline CDH1 mutation was found, it tells us that an early chapter in the story was loss of the wild-type allele of this gene, probably coinciding with biallelic loss of the TP53 gene (encoding cellular tumor antigen p53) or preceding it. Thus, mutation of CDH1 and TP53 are early events that probably drove tumor initiation and set the ball rolling. But why does the metastasis lack the FGFR2 amplification? This is most likely explained by the early dissemination of tumor cells from the primary lesion, which was removed by gastrectomy at presentation, to the metastatic site in the ovary, with these cells lying dormant, only to be reanimated years later by loss of TGFBR2. An alternative scenario could be that loss of TGFBR2 helped a cancer cell transit from the primary tumor to the metastatic site, where it lay in wait - either way, distal dissemination of the tumor must have been an early event occurring before removal of the primary.Figure 1

Bottom Line: Deep-sequencing of a primary tumor and metastasis from a single patient, and functional validation in culture, reveals that TGFBR2 and FGFR2 act as drivers of gastric cancer.

View Article: PubMed Central - PubMed

ABSTRACT
Deep-sequencing of a primary tumor and metastasis from a single patient, and functional validation in culture, reveals that TGFBR2 and FGFR2 act as drivers of gastric cancer.

Show MeSH
Related in: MedlinePlus