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Low-grade prostate cancer diverges early from high grade and metastatic disease.

VanderWeele DJ, Brown CD, Taxy JB, Gillard M, Hatcher DM, Tom WR, Stadler WM, White KP - Cancer Sci. (2014)

Bottom Line: Notably, mutations in cancer-associated genes and the p53 signaling pathway were found exclusively in high-grade foci and metastases.The pattern of mutations is consistent with early divergence between low- and high-grade foci and late divergence between high-grade foci and metastases.These data provide insights into the development of high-grade and metastatic prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA; Department of Medicine, University of Chicago, Chicago, Illinois, USA.

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Mutation characteristics. (a) Number of high-confidence somatic mutations across all foci. Non-silent, non-silent mutations; Unique, number of unique genes harboring a non-silent mutation; Reported, gene reported to be mutated in references 9–12 and 14. (b) Spectrum of unique high confidence somatic mutations across all foci. (c) Number of high-confidence somatic mutation types in all prostate samples. L, low-grade focus; H, high-grade focus; M, metastatic focus; NS, nonsynonymous; SYN, synonymous; UTR3, 3′ untranslated region; UTR5, 5′ untranslated region; SJ, splice junction; STOP, premature stop codon. (d) Confirmation of high-confidence somatic mutations with capillary sequencing by number of total and variant reads (gray, not confirmed; black, confirmed). Confirmation rate, 0.85.
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fig02: Mutation characteristics. (a) Number of high-confidence somatic mutations across all foci. Non-silent, non-silent mutations; Unique, number of unique genes harboring a non-silent mutation; Reported, gene reported to be mutated in references 9–12 and 14. (b) Spectrum of unique high confidence somatic mutations across all foci. (c) Number of high-confidence somatic mutation types in all prostate samples. L, low-grade focus; H, high-grade focus; M, metastatic focus; NS, nonsynonymous; SYN, synonymous; UTR3, 3′ untranslated region; UTR5, 5′ untranslated region; SJ, splice junction; STOP, premature stop codon. (d) Confirmation of high-confidence somatic mutations with capillary sequencing by number of total and variant reads (gray, not confirmed; black, confirmed). Confirmation rate, 0.85.

Mentions: Three hundred and one somatic mutations were identified across 10 foci (Table S2). Of these, 71 were synonymous and unlikely to alter gene function (Fig. 2a). Of 174 unique genes harboring somatic mutations that were likely to be functional, 73 were not reported in five previous reports of mutations in localized and advanced disease.(9)– (12,14) The majority of variants identified were transitions leading to nonsynonymous mutations (Fig. 2b,c), as expected. A subset of 20 high-confidence somatic mutations was confirmed in tumor and uninvolved tissue with capillary sequencing (Fig. 2d). Those that were not confirmed by capillary sequencing had low variant allele frequency and were approximately the level of detection for capillary sequencing (˜20%). Nevertheless, the mutation (0.82/Mb) and validation rate (85%) using fixed prostate specimens in the present study are similar to previous reports (0.9/Mb and 91%, respectively) using frozen tissue.(9) The high fidelity of this sequencing supports the use of formalin-fixed tissue for next-generation sequencing studies.


Low-grade prostate cancer diverges early from high grade and metastatic disease.

VanderWeele DJ, Brown CD, Taxy JB, Gillard M, Hatcher DM, Tom WR, Stadler WM, White KP - Cancer Sci. (2014)

Mutation characteristics. (a) Number of high-confidence somatic mutations across all foci. Non-silent, non-silent mutations; Unique, number of unique genes harboring a non-silent mutation; Reported, gene reported to be mutated in references 9–12 and 14. (b) Spectrum of unique high confidence somatic mutations across all foci. (c) Number of high-confidence somatic mutation types in all prostate samples. L, low-grade focus; H, high-grade focus; M, metastatic focus; NS, nonsynonymous; SYN, synonymous; UTR3, 3′ untranslated region; UTR5, 5′ untranslated region; SJ, splice junction; STOP, premature stop codon. (d) Confirmation of high-confidence somatic mutations with capillary sequencing by number of total and variant reads (gray, not confirmed; black, confirmed). Confirmation rate, 0.85.
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fig02: Mutation characteristics. (a) Number of high-confidence somatic mutations across all foci. Non-silent, non-silent mutations; Unique, number of unique genes harboring a non-silent mutation; Reported, gene reported to be mutated in references 9–12 and 14. (b) Spectrum of unique high confidence somatic mutations across all foci. (c) Number of high-confidence somatic mutation types in all prostate samples. L, low-grade focus; H, high-grade focus; M, metastatic focus; NS, nonsynonymous; SYN, synonymous; UTR3, 3′ untranslated region; UTR5, 5′ untranslated region; SJ, splice junction; STOP, premature stop codon. (d) Confirmation of high-confidence somatic mutations with capillary sequencing by number of total and variant reads (gray, not confirmed; black, confirmed). Confirmation rate, 0.85.
Mentions: Three hundred and one somatic mutations were identified across 10 foci (Table S2). Of these, 71 were synonymous and unlikely to alter gene function (Fig. 2a). Of 174 unique genes harboring somatic mutations that were likely to be functional, 73 were not reported in five previous reports of mutations in localized and advanced disease.(9)– (12,14) The majority of variants identified were transitions leading to nonsynonymous mutations (Fig. 2b,c), as expected. A subset of 20 high-confidence somatic mutations was confirmed in tumor and uninvolved tissue with capillary sequencing (Fig. 2d). Those that were not confirmed by capillary sequencing had low variant allele frequency and were approximately the level of detection for capillary sequencing (˜20%). Nevertheless, the mutation (0.82/Mb) and validation rate (85%) using fixed prostate specimens in the present study are similar to previous reports (0.9/Mb and 91%, respectively) using frozen tissue.(9) The high fidelity of this sequencing supports the use of formalin-fixed tissue for next-generation sequencing studies.

Bottom Line: Notably, mutations in cancer-associated genes and the p53 signaling pathway were found exclusively in high-grade foci and metastases.The pattern of mutations is consistent with early divergence between low- and high-grade foci and late divergence between high-grade foci and metastases.These data provide insights into the development of high-grade and metastatic prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA; Department of Medicine, University of Chicago, Chicago, Illinois, USA.

Show MeSH
Related in: MedlinePlus