case_study_SMAD4

Basic information

• SMAD4 is
  • a TSG
    
  • tumor type specific: colorectal, pancreatic and small intestine
    
  • involved in signal transduction of the transforming growth factor-beta(TGF\(\beta\))

The following info is derived from OMIM page

About 90% of human pancreatic carcinomas show allelic loss at 18q.
Hahn et al. (1996) reported the identification of a putative tumor suppressor gene on chromosome 18q21.1 that may be a candidate for pancreatic carcinoma. The gene was homozygously deleted in 25 of 84 tumors and mutations were identified as somatic mutations in 6 of 27 carcinomas that lacked deletions.

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SMAD4 in TCGA pancreatic adenocarcinoma

• PAAD cohort consists of 149 patients with sequencing data. Copy number alteration, mRNA expression, methylation data are also available at cbioportal.

Alterations

Considering 23 deep deletions, 19 nonsense mutations, 14 missense mutations and 1 inframe deletion, SMAD4 is altered in 57 of 149(38%) samples as displayed in the following oncoprint figure. By adding additional “shallow deletion” samples(not shown in figure), The portion of samples with SMAD4 alteration would reach as high as 113 out of 149 (76%) .

The data reveals that the deletion of SMAD4 is prevalent in pancreatic cancer through copy number deletion or nonsense mutation. This is comparable with observations reported by Hahn et al. (1996).

Copy number variation

• The copy number alteration calculated using GISTIC(Mermel et al. 2011) discussed here can also be validated using mRNA expression data.
  • note that samples with truncating mutations fall in the “shallow deletion” column.
  • Deep deletion: 23, shallow deletion: 90. SMAD4 deletion is prevalent (113 of 149 samples, 0.7583893% ) in pancreatic cancer cohort.

Regulatory network

SMAD4’s 50 most frequently altered neighbor genes (2% or more samples) are displayed in a directed graph:

• Three colored edges are
  • blue: Controls State Change of
  • green: Controls Expression of
  • brown: In Complex With
• The white to color gradient represents the total frequency of alterations in the cohort.
  
• shallow deletion is not counted

It’s obvious that SMAD4 is the most altered gene in this network.

Summary

SMAD4 is significantly altered in pancreatic cancer. 113 of 149 samples have SMAD4 deletions.

Reference

Hahn, S. A., M. Schutte, A. T. M. S. Hoque, C. A. Moskaluk, L. T. da Costa, E. Rozenblum, C. L. Weinstein, et al. 1996. “DPC4, A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1.” Science 271 (5247): 350–53. doi:10.1126/science.271.5247.350.

Mermel, Craig H, Steven E Schumacher, Barbara Hill, Matthew L Meyerson, Rameen Beroukhim, and Gad Getz. 2011. “GISTIC2.0 Facilitates Sensitive and Confident Localization of the Targets of Focal Somatic Copy-Number Alteration in Human Cancers.” Genome Biology 12 (4): R41. doi:10.1186/gb-2011-12-4-r41.