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. 2011 Jul 25:9:119.
doi: 10.1186/1479-5876-9-119.

Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine

Joanna D Holbrook  1 , Joel S Parker, Kathleen T Gallagher, Wendy S Halsey, Ashley M Hughes, Victor J Weigman, Peter F Lebowitz, Rakesh Kumar
Affiliations

Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine

Joanna D Holbrook et al. J Transl Med. .

Abstract

Background: Globally, gastric cancer is the second most common cause of cancer-related death, with the majority of the health burden borne by economically less-developed countries.

Methods: Here, we report a genetic characterization of 50 gastric adenocarcinoma samples, using affymetrix SNP arrays and Illumina mRNA expression arrays as well as Illumina sequencing of the coding regions of 384 genes belonging to various pathways known to be altered in other cancers.

Results: Genetic alterations were observed in the WNT, Hedgehog, cell cycle, DNA damage and epithelial-to-mesenchymal-transition pathways.

Conclusions: The data suggests targeted therapies approved or in clinical development for gastric carcinoma would be of benefit to ~22% of the patients studied. In addition, the novel mutations detected here, are likely to influence clinical response and suggest new targets for drug discovery.

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Figures

Figure 1
Figure 1
View of CNV aberrations across all 50 gastric carcinoma samples, for each autosome. The y-axis corresponds to the sum of the number of positive or negative changes for a particular segment with the log2 ratio of those change. Areas with increased or decreased copy number consistent throughout all the samples analysed or very large changes in few samples will show large positive and negative change sizes. Each dot or segment in figure is colored by sample. The colour code is arbitrary with each of the 50 cancer samples being assigned a colour. Amplified segments include chromosome 8q, 20q, 20p, 3q, 7p, and 1q.
Figure 2
Figure 2
Expression of example genes from each amplified chromosomal region across study samples confirmed by Q-PCR. Red dots denote cancer samples and white dots denote normal samples. The y-axis denotes the mRNA abundance.
Figure 3
Figure 3
Mutational profile of samples. Tissue samples are displayed across the top and annotations relevant to them are in columns below. Red boxes denote DNA amplification and concordant mRNA overexpression, orange boxes denote RNA overexpression with no evidence of DNA amplification, red dots denote DNA loss. Blue boxes denote somatic nonsynonymous mutation validated by Sanger sequencing and purple boxes denote nonsynonymous somatic mutations, observed in the Illumina data with no attempt to confirm by Sanger sequencing. Amino changes are noted in the boxes and changes leading to loss or gain of a stop codon are in red text.
Figure 4
Figure 4
Bar chart of rate of deleterious mutations across gene sequenced. Genes sequenced are shown on the x-axis. The number of deleterious somatic nonsynonymous mutations observed in each gene/number of amino acids in each CDS in plotted.
Figure 5
Figure 5
Transcriptional signatures across samples. Clustered heatmap showing expression of A wnt signature genes and B hedgehog signature genes, across samples in the study. All expression values are Zscore normalized. Zscore <-1 are blue, Z-score > 1 are red with a graded coloring through white at 0. Sample names are on the x-axis, they are clustered by expression pattern and samples with high signature scores are to the right. Samples with somatic nonsynonymous APC mutations (A) or PTCH1 mutations (B) and denoted by an asterisk above the heatmaps. WNT signature genes (top to bottom): FSTL1, DACT1, CD99, LMNA, SERPINE1, TNFAIP3, GNAI2, ID2, MVP, ACTN4, CAPN1, LUZP1, MTA1, RPS19, PTPRE, AXIN2, NKD2, SFRS6, CCND1, SCAP, CPSF4, SENP2, DKK1, PRKCSH, SLC1A5, HDGF, CBX3, SCML1, PCNA, RPS11, SNRPA1, TGM2, LY6E, IFITM1, NSMAF, TCF20, BCAP31, AXIN1, AGRN, PLEKHA1, SLC2A1, CTNNB1, EIF5A, IMPDH2, GSK3B, PFN1, UBE, MAP3K11, ARHGDIA, HNRPUL1, FLOT2, GYPC, NCOA3, CENTB1, SYK, POLR2A, KRT5, DHX36, ELF1, SMG2, FGD6, MAPKAP1, LOC389435, RPL27A, SRP19, RPL39L, SFRS2IP, FUSIP1; Hedgehog signature genes (top to bottom): LRFN4, JAG2, RPL29, WNT5A, SNAI2, FST, MYCN, BMP4, CCND1, BMI1, CFLAR, PRDM1, GREM1, FOXF1, CCND2, CD44.
Figure 6
Figure 6
Expression of KLK6 across study samples confirmed by q-PCR. Red dots denote cancer samples and white dots denote normal samples. Patient IDs are arranged on the x-axis. The y-axis is the mRNA abundance.
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