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Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data.

Haricharan S, Bainbridge MN, Scheet P, Brown PH - Breast Cancer Res. Treat. (2014)

Bottom Line: Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes.Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival.Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301439, Houston, TX, 77030-1439, USA, sharicharan@mdanderson.org.

ABSTRACT
Breast cancer is one of the most commonly diagnosed cancers in women. While there are several effective therapies for breast cancer and important single gene prognostic/predictive markers, more than 40,000 women die from this disease every year. The increasing availability of large-scale genomic datasets provides opportunities for identifying factors that influence breast cancer survival in smaller, well-defined subsets. The purpose of this study was to investigate the genomic landscape of various breast cancer subtypes and its potential associations with clinical outcomes. We used statistical analysis of sequence data generated by the Cancer Genome Atlas initiative including somatic mutation load (SML) analysis, Kaplan-Meier survival curves, gene mutational frequency, and mutational enrichment evaluation to study the genomic landscape of breast cancer. We show that ER(+), but not ER(-), tumors with high SML associate with poor overall survival (HR = 2.02). Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes. While it is known that somatic mutations in specific genes affect breast cancer survival, this study is the first to identify that SML may constitute an important global signature for a subset of ER(+) tumors prone to high mortality. Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival. Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies.

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ER+ HML tumors are enriched for mutations in MMR and NER pathway genes. a, b Venn diagrams indicating genes from the specified DDR pathway that are mutated in either the HML (red) or LML (blue) subset of ER+ tumors, in both (purple) and in neither (white). Increasing font size indicates an increasing proportion of tumors with mutations in the specific gene. c Bar graph depicting the average SML in tumors with specified mutational status. Student’s t test with Holm’s adjustment for multiple comparisons was used to define p-values. Chkpt, genes from the DNA damage checkpoint; NL, tumors with no identified mutations in genes from the specified pathway; mut, tumors with identified non-silent mutations in genes from the specified pathway; ns not significant
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Fig3: ER+ HML tumors are enriched for mutations in MMR and NER pathway genes. a, b Venn diagrams indicating genes from the specified DDR pathway that are mutated in either the HML (red) or LML (blue) subset of ER+ tumors, in both (purple) and in neither (white). Increasing font size indicates an increasing proportion of tumors with mutations in the specific gene. c Bar graph depicting the average SML in tumors with specified mutational status. Student’s t test with Holm’s adjustment for multiple comparisons was used to define p-values. Chkpt, genes from the DNA damage checkpoint; NL, tumors with no identified mutations in genes from the specified pathway; mut, tumors with identified non-silent mutations in genes from the specified pathway; ns not significant

Mentions: Using these conservative thresholds, we found no significant enrichment for DDR mutations overall in HMLs over LMLs (Fig. 2a, b). However, mutations in MMR pathway genes occurred in 16-fold more tumors and occurred at 7-fold higher frequency in HML than in LML ER+ tumors indicating significant enrichment over and above our set thresholds (Fig. 2a, b). Uniquely, every gene specific to the MMR pathway was mutated at least once in the HML subset of ER+ tumors (Fig. 3a). Genes from the single-strand break repair pathway, NER, were also mutated in 7-fold more HML tumors and at 2.5-fold higher frequency relative to the LML ER+ tumors (Fig. 3a). Notably, there was no significant enrichment in the HMLs in DNA damage checkpoint genes (Fig. 2a, b). Some genes from the double-strand break repair pathways, e.g., BLM and XRCC4, are mutated at higher frequencies and in more tumors in the HML subset than in the LML subset, but this enrichment is not significant (Figs. 3b; 2a, b).Fig. 3


Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data.

Haricharan S, Bainbridge MN, Scheet P, Brown PH - Breast Cancer Res. Treat. (2014)

ER+ HML tumors are enriched for mutations in MMR and NER pathway genes. a, b Venn diagrams indicating genes from the specified DDR pathway that are mutated in either the HML (red) or LML (blue) subset of ER+ tumors, in both (purple) and in neither (white). Increasing font size indicates an increasing proportion of tumors with mutations in the specific gene. c Bar graph depicting the average SML in tumors with specified mutational status. Student’s t test with Holm’s adjustment for multiple comparisons was used to define p-values. Chkpt, genes from the DNA damage checkpoint; NL, tumors with no identified mutations in genes from the specified pathway; mut, tumors with identified non-silent mutations in genes from the specified pathway; ns not significant
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Related In: Results  -  Collection

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Fig3: ER+ HML tumors are enriched for mutations in MMR and NER pathway genes. a, b Venn diagrams indicating genes from the specified DDR pathway that are mutated in either the HML (red) or LML (blue) subset of ER+ tumors, in both (purple) and in neither (white). Increasing font size indicates an increasing proportion of tumors with mutations in the specific gene. c Bar graph depicting the average SML in tumors with specified mutational status. Student’s t test with Holm’s adjustment for multiple comparisons was used to define p-values. Chkpt, genes from the DNA damage checkpoint; NL, tumors with no identified mutations in genes from the specified pathway; mut, tumors with identified non-silent mutations in genes from the specified pathway; ns not significant
Mentions: Using these conservative thresholds, we found no significant enrichment for DDR mutations overall in HMLs over LMLs (Fig. 2a, b). However, mutations in MMR pathway genes occurred in 16-fold more tumors and occurred at 7-fold higher frequency in HML than in LML ER+ tumors indicating significant enrichment over and above our set thresholds (Fig. 2a, b). Uniquely, every gene specific to the MMR pathway was mutated at least once in the HML subset of ER+ tumors (Fig. 3a). Genes from the single-strand break repair pathway, NER, were also mutated in 7-fold more HML tumors and at 2.5-fold higher frequency relative to the LML ER+ tumors (Fig. 3a). Notably, there was no significant enrichment in the HMLs in DNA damage checkpoint genes (Fig. 2a, b). Some genes from the double-strand break repair pathways, e.g., BLM and XRCC4, are mutated at higher frequencies and in more tumors in the HML subset than in the LML subset, but this enrichment is not significant (Figs. 3b; 2a, b).Fig. 3

Bottom Line: Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes.Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival.Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301439, Houston, TX, 77030-1439, USA, sharicharan@mdanderson.org.

ABSTRACT
Breast cancer is one of the most commonly diagnosed cancers in women. While there are several effective therapies for breast cancer and important single gene prognostic/predictive markers, more than 40,000 women die from this disease every year. The increasing availability of large-scale genomic datasets provides opportunities for identifying factors that influence breast cancer survival in smaller, well-defined subsets. The purpose of this study was to investigate the genomic landscape of various breast cancer subtypes and its potential associations with clinical outcomes. We used statistical analysis of sequence data generated by the Cancer Genome Atlas initiative including somatic mutation load (SML) analysis, Kaplan-Meier survival curves, gene mutational frequency, and mutational enrichment evaluation to study the genomic landscape of breast cancer. We show that ER(+), but not ER(-), tumors with high SML associate with poor overall survival (HR = 2.02). Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes. While it is known that somatic mutations in specific genes affect breast cancer survival, this study is the first to identify that SML may constitute an important global signature for a subset of ER(+) tumors prone to high mortality. Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival. Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies.

Show MeSH
Related in: MedlinePlus