Combinatorial patterns of somatic gene mutations in cancer

Abstract

Cancer is a complex process in which the abnormalities of many genes appear to be involved. The combinatorial patterns of gene mutations may reveal the functional relations between genes and pathways in tumorigenesis as well as identify targets for treatment. We examined the patterns of somatic mutations of cancers from Catalog of Somatic Mutations in Cancer (COSMIC), a large-scale database curated by the Wellcome Trust Sanger Institute. The frequently mutated genes are well-known oncogenes and tumor suppressors that are involved in generic processes of cell-cycle control, signal transduction, and stress responses. These "signatures" of gene mutations are heterogeneous when the cancers from different tissues are compared. Mutations in genes functioning in different pathways can occur in the same cancer (i.e., co-occur), whereas those in genes functioning in the same pathway are rarely mutated in the same sample. This observation supports the view of tumorigenesis as derived from a process like Darwinian evolution. However, certain combinatorial mutational patterns violate these simple rules and demonstrate tissue-specific variations. For instance, mutations of genes in the Ras and Wnt pathways tend to co-occur in the large intestine but are mutually exclusive in cancers of the pancreas. The relationships between mutations in different samples of a cancer can also reveal the temporal orders of mutational events. In addition, the observed mutational patterns suggest candidates of new cosequencing targets that can either reveal novel patterns or validate the predictions deduced from existing patterns. These combinatorial mutational patterns provide guiding information for the ongoing cancer genome projects.

Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression

“…Clinical evidence is compelling for histologic progression of breast cancer through atypical hyperplasia, ductal carcinoma in situ (DCIS), invasive ductal carcinoma, and metastatic stages. 1 Such histopathologic progression studies and mutational profiling of epithelial cancers 2,3 suggest that acquisition of invasive potential is a relatively late event. However, genomic data analyses have revealed that most tumor cell gene expression changes occur at the transition from normal to DCIS, with few additional changes in expression occurring at the transition from DCIS to overt invasive disease.…”

Role of Tumor Tissue Analysis in Rectal Cancer Pharmacogenetics

“…In the same way, the existence of mutually exclusive mutations in the same tumor type highlights the importance of differentiate subgroups. These observations reveal the importance of identify the tumor specific genetic pattern (Yeang et al, 2008).…”

“…As we have seen this mutagenic mechanism remains in the tumor after cancer treatment. Yeang et al (2008) detected significant different mutational patterns between cell lines and tumor samples. The effect of a polymorphism or somatic mutation in a protein is firstly tested in a cell line.…”

Activating Mutations and Targeted Therapy in Cancer

“…BRAF has been discovered to be the most commonly mutated oncogene in melanoma (50-60%) (Davies, Bignell et al 2002), papillary thyroid carcinoma (36-53%) (Yeang , McCormick et al 2008), colon carcinoma (57%), serous ovarian carcinoma (~30%) (Yeang , McCormick et al 2008), and hairy cell leukemia (100%) (Tiacci, Trifonov et al 2011). To date, >60 distinct mutations in the BRAF gene have been identified (Table 1) (Garnett and Marais 2004;Catalog of Somatic Mutations in Cancer: www.sanger.ac.uk/genetics/CGP/cosmic/).…”