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Absolute quantification of somatic DNA alterations in human cancer.

Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, Laird PW, Onofrio RC, Winckler W, Weir BA, Beroukhim R, Pellman D, Levine DA, Lander ES, Meyerson M, Getz G - Nat. Biotechnol. (2012)

Bottom Line: The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations.We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs.This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12.

View Article: PubMed Central - PubMed

Affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. scarter@broadinstitute.org

ABSTRACT
We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.

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Genetic and clinical associations with genome doubling in primary HGS-OvCa samplesa-e, Colors correspond to putative genome doubling status, as indicated. Significance codes: **– P < 10-5, * – P < 0.05, NS – P > 0.05.a-c, Number of mutations in indicated classes as a function of genome doublings. P-values were calculated with the two-sided Wilcoxin rank-sum test comparing samples with 0 and 1 genome doublings. Error bars indicate standard errors of the means.d,P-values were calculated with the two-sided Wilcoxin rank-sum test.e,P-values were calculated using the log-rank test.
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Figure 7: Genetic and clinical associations with genome doubling in primary HGS-OvCa samplesa-e, Colors correspond to putative genome doubling status, as indicated. Significance codes: **– P < 10-5, * – P < 0.05, NS – P > 0.05.a-c, Number of mutations in indicated classes as a function of genome doublings. P-values were calculated with the two-sided Wilcoxin rank-sum test comparing samples with 0 and 1 genome doublings. Error bars indicate standard errors of the means.d,P-values were calculated with the two-sided Wilcoxin rank-sum test.e,P-values were calculated using the log-rank test.

Mentions: We next sought to correlate whole-genome doubling occurrence in ovarian carcinoma with other genetic and clinical features. Genome-doubled samples showed a higher incidence of heterozygous mutations, but correcting for sample ploidy removed this effect (Fig. 7a), suggesting that the per-base mutation rates are equivalent. Clonal mutations at multiplicity > 1 were approximately ten-fold more prevalent in doubled samples; many of these events likely occurred prior to the doubling event. Genome-doubled samples had a lower frequency of homozygous deletions (Fig. 7b) and a two-fold lower rate of clonal homozygous mutations (P = 1.55×10-8, Fig. 7c). We expect that many of the observed homozygous alterations in the doubled samples were fixed prior to genome doubling.


Absolute quantification of somatic DNA alterations in human cancer.

Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, Laird PW, Onofrio RC, Winckler W, Weir BA, Beroukhim R, Pellman D, Levine DA, Lander ES, Meyerson M, Getz G - Nat. Biotechnol. (2012)

Genetic and clinical associations with genome doubling in primary HGS-OvCa samplesa-e, Colors correspond to putative genome doubling status, as indicated. Significance codes: **– P < 10-5, * – P < 0.05, NS – P > 0.05.a-c, Number of mutations in indicated classes as a function of genome doublings. P-values were calculated with the two-sided Wilcoxin rank-sum test comparing samples with 0 and 1 genome doublings. Error bars indicate standard errors of the means.d,P-values were calculated with the two-sided Wilcoxin rank-sum test.e,P-values were calculated using the log-rank test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383288&req=5

Figure 7: Genetic and clinical associations with genome doubling in primary HGS-OvCa samplesa-e, Colors correspond to putative genome doubling status, as indicated. Significance codes: **– P < 10-5, * – P < 0.05, NS – P > 0.05.a-c, Number of mutations in indicated classes as a function of genome doublings. P-values were calculated with the two-sided Wilcoxin rank-sum test comparing samples with 0 and 1 genome doublings. Error bars indicate standard errors of the means.d,P-values were calculated with the two-sided Wilcoxin rank-sum test.e,P-values were calculated using the log-rank test.
Mentions: We next sought to correlate whole-genome doubling occurrence in ovarian carcinoma with other genetic and clinical features. Genome-doubled samples showed a higher incidence of heterozygous mutations, but correcting for sample ploidy removed this effect (Fig. 7a), suggesting that the per-base mutation rates are equivalent. Clonal mutations at multiplicity > 1 were approximately ten-fold more prevalent in doubled samples; many of these events likely occurred prior to the doubling event. Genome-doubled samples had a lower frequency of homozygous deletions (Fig. 7b) and a two-fold lower rate of clonal homozygous mutations (P = 1.55×10-8, Fig. 7c). We expect that many of the observed homozygous alterations in the doubled samples were fixed prior to genome doubling.

Bottom Line: The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations.We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs.This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12.

View Article: PubMed Central - PubMed

Affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. scarter@broadinstitute.org

ABSTRACT
We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.

Show MeSH
Related in: MedlinePlus