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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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HML subset of ER+ breast tumors is associated with poor clinical outcome. a Index plot. Median and mean SMLs of each population are indicated with red lines. b–e Kaplan–Meier survival curves of all breast tumors (b) and the HML (red) and LML (blue) subsets of: c ER+ breast cancer; d ER− breast cancer; and e a comparison between ER+ HML, ER+ LML, and ER− (black) breast cancer. The log-rank test was used to determine p-values
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Fig1: HML subset of ER+ breast tumors is associated with poor clinical outcome. a Index plot. Median and mean SMLs of each population are indicated with red lines. b–e Kaplan–Meier survival curves of all breast tumors (b) and the HML (red) and LML (blue) subsets of: c ER+ breast cancer; d ER− breast cancer; and e a comparison between ER+ HML, ER+ LML, and ER− (black) breast cancer. The log-rank test was used to determine p-values

Mentions: Our sample set comprises 762 invasive breast tumors from the TCGA dataset. Immunohistochemical analysis shows that the majority of these tumors (73.4 %) are ER+ (Table 3). The mean SML is 67.23 mutations per tumor (Table 3); however, ER− tumors have a significantly higher SML than ER+ tumors (p < 0.0001; Fig. 1a). Furthermore, ER+ and ER− tumors are characterized by marked differences in SML distribution. ER+ tumors have a median SML of 46 (Fig. 1a) and a mean SML of 62.7, with a small subset of these tumors carrying significantly high mutation loads (HMLs) (Fig. 1a). Conversely, ER− tumors lack a distinct high mutation subset, instead almost half (42 %) of the tumors carry mutation loads higher than the mean SML (Fig. 1a).Table 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)

HML subset of ER+ breast tumors is associated with poor clinical outcome. a Index plot. Median and mean SMLs of each population are indicated with red lines. b–e Kaplan–Meier survival curves of all breast tumors (b) and the HML (red) and LML (blue) subsets of: c ER+ breast cancer; d ER− breast cancer; and e a comparison between ER+ HML, ER+ LML, and ER− (black) breast cancer. The log-rank test was used to determine p-values
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4061465&req=5

Fig1: HML subset of ER+ breast tumors is associated with poor clinical outcome. a Index plot. Median and mean SMLs of each population are indicated with red lines. b–e Kaplan–Meier survival curves of all breast tumors (b) and the HML (red) and LML (blue) subsets of: c ER+ breast cancer; d ER− breast cancer; and e a comparison between ER+ HML, ER+ LML, and ER− (black) breast cancer. The log-rank test was used to determine p-values
Mentions: Our sample set comprises 762 invasive breast tumors from the TCGA dataset. Immunohistochemical analysis shows that the majority of these tumors (73.4 %) are ER+ (Table 3). The mean SML is 67.23 mutations per tumor (Table 3); however, ER− tumors have a significantly higher SML than ER+ tumors (p < 0.0001; Fig. 1a). Furthermore, ER+ and ER− tumors are characterized by marked differences in SML distribution. ER+ tumors have a median SML of 46 (Fig. 1a) and a mean SML of 62.7, with a small subset of these tumors carrying significantly high mutation loads (HMLs) (Fig. 1a). Conversely, ER− tumors lack a distinct high mutation subset, instead almost half (42 %) of the tumors carry mutation loads higher than the mean SML (Fig. 1a).Table 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