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A pathway-centric survey of somatic mutations in Chinese patients with colorectal carcinomas.

Ling C, Wang L, Wang Z, Xu L, Sun L, Yang H, Li WD, Wang K - PLoS ONE (2015)

Bottom Line: Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients.Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients.We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.

View Article: PubMed Central - PubMed

Affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, United States of America; Laboratory of Clinical Genetics, Peking Union Medical College Hospital, Beijing, 100730, China; Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.

ABSTRACT
Previous genetic studies on colorectal carcinomas (CRC) have identified multiple somatic mutations in four candidate pathways (TGF-β, Wnt, P53 and RTK-RAS pathways) on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes. In this study, to evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and PolyPhen-2 to assess potentially functional mutations. We discovered 3 new somatic mutations in gene APC, TCF7L2, and PIK3CA that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients. While most were previously reported in CRC, one mutation in PTEN was reported only in malignant endometrium cancer. Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.

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Sanger sequencing validated somatic mutations.A, somatic mutations which had been reported in CRC or other cancers. B, novel somatic mutations that discovered in our CRC patients.
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pone.0116753.g003: Sanger sequencing validated somatic mutations.A, somatic mutations which had been reported in CRC or other cancers. B, novel somatic mutations that discovered in our CRC patients.

Mentions: Based on our analytical strategy (Fig. 1), we identified multiple genes in the TGFβ, Wnt signaling, P53 and RTK-RAS pathways that carried somatic mutations in a fraction of the cases (Fig. 2). Overall, 25 point mutations in 11 genes were reported in previous studies and were documented in the COSMIC v67 database [35] (S4 Table). The APC gene in Wnt pathway has relatively high levels of somatic mutations, compared to genes in the TGFβ, P53 and RTK-RAS pathways (S1 Table). We confirmed the recurrent somatic mutations in the SMAD4 gene, including a recurrent point mutation of (c.1082G>A, p.R361H) [36] in 2 of our CRC cases. A nonsense point mutation in the tumor suppressor gene APC (c.4013C>G, p.S1338X) was previously reported in colon cancer [37], but was found in one of our cases with rectum cancer. Reported mutations in gene FBXW7 (c.1514G>A, p.R505H) [38] and BRAF (c.1396G>A, p.G466R) (COSMIC) were also identified in our study. Meanwhile, a somatic mutation in the PTEN gene (c.415T>G, p.L139V) was previously found in endometrium cancer [39], but was identified in one of our cases with colon cancer. All these mutations have been validated by Sanger sequencing (Fig. 3A).


A pathway-centric survey of somatic mutations in Chinese patients with colorectal carcinomas.

Ling C, Wang L, Wang Z, Xu L, Sun L, Yang H, Li WD, Wang K - PLoS ONE (2015)

Sanger sequencing validated somatic mutations.A, somatic mutations which had been reported in CRC or other cancers. B, novel somatic mutations that discovered in our CRC patients.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4305320&req=5

pone.0116753.g003: Sanger sequencing validated somatic mutations.A, somatic mutations which had been reported in CRC or other cancers. B, novel somatic mutations that discovered in our CRC patients.
Mentions: Based on our analytical strategy (Fig. 1), we identified multiple genes in the TGFβ, Wnt signaling, P53 and RTK-RAS pathways that carried somatic mutations in a fraction of the cases (Fig. 2). Overall, 25 point mutations in 11 genes were reported in previous studies and were documented in the COSMIC v67 database [35] (S4 Table). The APC gene in Wnt pathway has relatively high levels of somatic mutations, compared to genes in the TGFβ, P53 and RTK-RAS pathways (S1 Table). We confirmed the recurrent somatic mutations in the SMAD4 gene, including a recurrent point mutation of (c.1082G>A, p.R361H) [36] in 2 of our CRC cases. A nonsense point mutation in the tumor suppressor gene APC (c.4013C>G, p.S1338X) was previously reported in colon cancer [37], but was found in one of our cases with rectum cancer. Reported mutations in gene FBXW7 (c.1514G>A, p.R505H) [38] and BRAF (c.1396G>A, p.G466R) (COSMIC) were also identified in our study. Meanwhile, a somatic mutation in the PTEN gene (c.415T>G, p.L139V) was previously found in endometrium cancer [39], but was identified in one of our cases with colon cancer. All these mutations have been validated by Sanger sequencing (Fig. 3A).

Bottom Line: Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients.Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients.We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.

View Article: PubMed Central - PubMed

Affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, United States of America; Laboratory of Clinical Genetics, Peking Union Medical College Hospital, Beijing, 100730, China; Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.

ABSTRACT
Previous genetic studies on colorectal carcinomas (CRC) have identified multiple somatic mutations in four candidate pathways (TGF-β, Wnt, P53 and RTK-RAS pathways) on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes. In this study, to evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and PolyPhen-2 to assess potentially functional mutations. We discovered 3 new somatic mutations in gene APC, TCF7L2, and PIK3CA that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients. While most were previously reported in CRC, one mutation in PTEN was reported only in malignant endometrium cancer. Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.

Show MeSH
Related in: MedlinePlus