Limits...
Protein domain-level landscape of cancer-type-specific somatic mutations.

Yang F, Petsalaki E, Rolland T, Hill DE, Vidal M, Roth FP - PLoS Comput. Biol. (2015)

Bottom Line: Identifying driver mutations and their functional consequences is critical to our understanding of cancer.While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains.Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Donnelly Centre, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.

ABSTRACT
Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we systematically examined tumor genomes from 21 cancer types to identify domains with high mutational density in specific tissues, the positions of mutational hotspots within these domains, and the functional and structural context where possible. While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains. Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors. For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer. Thus, to prioritize cancer mutations for further functional studies aimed at more precise cancer treatments, we have systematically correlated mutations and cancer types at the protein domain level.

Show MeSH

Related in: MedlinePlus

Distribution of mutated residues in FGFR.Sequence positions and frequencies of mutated residues in the FGFR protein are shown. Mutational hotspots for each cancer type are displayed as red dots. SMDs are shown as thicker boxes.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4368709&req=5

pcbi.1004147.g007: Distribution of mutated residues in FGFR.Sequence positions and frequencies of mutated residues in the FGFR protein are shown. Mutational hotspots for each cancer type are displayed as red dots. SMDs are shown as thicker boxes.

Mentions: For example, the fibroblast growth factor receptor 2 (FGFR2) is generally regarded as an oncoprotein in breast cancer[15]. Consistent with this view, we found a single hotspot (p.N549) for FGFR2 in breast cancer in the kinase domain, which had not been reported as a hotspot for breast cancer. A previous study of endometrial cancer[54] suggested FGFR2 to be a tumor suppressor protein. Supporting this view, we observed nine evenly-distributed mutated residues in the kinase domain in endometrial cancer, although we also confirm previous observation [54] of the p.N549 hotspot which is more suggestive of an oncoprotein. Four mutational hotspots in the Immunoglobulin I-set domain of FGFR2 were observed in colon cancer, which hints at a tumor suppression role for FGFR2 in colon cancer (Fig. 7).


Protein domain-level landscape of cancer-type-specific somatic mutations.

Yang F, Petsalaki E, Rolland T, Hill DE, Vidal M, Roth FP - PLoS Comput. Biol. (2015)

Distribution of mutated residues in FGFR.Sequence positions and frequencies of mutated residues in the FGFR protein are shown. Mutational hotspots for each cancer type are displayed as red dots. SMDs are shown as thicker boxes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4368709&req=5

pcbi.1004147.g007: Distribution of mutated residues in FGFR.Sequence positions and frequencies of mutated residues in the FGFR protein are shown. Mutational hotspots for each cancer type are displayed as red dots. SMDs are shown as thicker boxes.
Mentions: For example, the fibroblast growth factor receptor 2 (FGFR2) is generally regarded as an oncoprotein in breast cancer[15]. Consistent with this view, we found a single hotspot (p.N549) for FGFR2 in breast cancer in the kinase domain, which had not been reported as a hotspot for breast cancer. A previous study of endometrial cancer[54] suggested FGFR2 to be a tumor suppressor protein. Supporting this view, we observed nine evenly-distributed mutated residues in the kinase domain in endometrial cancer, although we also confirm previous observation [54] of the p.N549 hotspot which is more suggestive of an oncoprotein. Four mutational hotspots in the Immunoglobulin I-set domain of FGFR2 were observed in colon cancer, which hints at a tumor suppression role for FGFR2 in colon cancer (Fig. 7).

Bottom Line: Identifying driver mutations and their functional consequences is critical to our understanding of cancer.While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains.Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Donnelly Centre, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.

ABSTRACT
Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we systematically examined tumor genomes from 21 cancer types to identify domains with high mutational density in specific tissues, the positions of mutational hotspots within these domains, and the functional and structural context where possible. While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains. Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors. For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer. Thus, to prioritize cancer mutations for further functional studies aimed at more precise cancer treatments, we have systematically correlated mutations and cancer types at the protein domain level.

Show MeSH
Related in: MedlinePlus