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TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

View Article: PubMed Central - PubMed

ABSTRACT

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.

In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 05E010-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 05E010-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.

If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

No MeSH data available.


Kaplan-Meier curves for all combinations of rs10916264 genotype and TP53 status among pooled a) ER-positive and b) ER-negative BCAC cases.
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Figure 1: Kaplan-Meier curves for all combinations of rs10916264 genotype and TP53 status among pooled a) ER-positive and b) ER-negative BCAC cases.

Mentions: To better illustrate the interaction results, we plotted Kaplan-Meier curves of all genotype-IHC combinations (Figure 1). The plots indicate that specifically the rs10916264 AA ancestral genotype (genotype frequency 23.2%, allele frequency 48.0%; used as reference allele in the interaction analysis) associates with worse survival among ER-positive, TP53-positive cases, while all other genotype-IHC combinations are clustered together. We therefore also analyzed this SNP using the recessive genetic model, using G as the reference allele, and calculated Cox proportional hazard models in TP53- and ER-based subgroups. In ER-positive, TP53-positive breast cancer cases, the homozygous rs10916264 AA genotype associated with a HR of 2.36 (95% confidence interval [C.I.] 1.45 – 3.82; Figure 2a), while in ER-positive, TP53-negative cases, the homozygous genotype did not associate with a difference in survival at all (HR 0.80, 95% C.I. 0.62 – 1.02; Figure 2a). When the rs10916264:TP53 interaction model was calculated separately for each study, all studies were in agreement on the direction of the interaction term (I2 = 11.72%, Q test for heterogeneity p = 0.3927; Figure 3). The interaction remained statistically significant (p = 2.6 × 10-4) when adjuvant endocrine therapy was included in the Cox model, and the interaction exists at a nominally significant level even among ER-positive cases not treated with endocrine therapy (n = 843, 140 events, p = 0.04). The interaction was also independent of adjuvant chemotherapy treatment with nominally significant interaction p-values in both chemotherapy-treated and untreated groups (p = 0.033 and 0.028, respectively).


TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer
Kaplan-Meier curves for all combinations of rs10916264 genotype and TP53 status among pooled a) ER-positive and b) ER-negative BCAC cases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5392336&req=5

Figure 1: Kaplan-Meier curves for all combinations of rs10916264 genotype and TP53 status among pooled a) ER-positive and b) ER-negative BCAC cases.
Mentions: To better illustrate the interaction results, we plotted Kaplan-Meier curves of all genotype-IHC combinations (Figure 1). The plots indicate that specifically the rs10916264 AA ancestral genotype (genotype frequency 23.2%, allele frequency 48.0%; used as reference allele in the interaction analysis) associates with worse survival among ER-positive, TP53-positive cases, while all other genotype-IHC combinations are clustered together. We therefore also analyzed this SNP using the recessive genetic model, using G as the reference allele, and calculated Cox proportional hazard models in TP53- and ER-based subgroups. In ER-positive, TP53-positive breast cancer cases, the homozygous rs10916264 AA genotype associated with a HR of 2.36 (95% confidence interval [C.I.] 1.45 – 3.82; Figure 2a), while in ER-positive, TP53-negative cases, the homozygous genotype did not associate with a difference in survival at all (HR 0.80, 95% C.I. 0.62 – 1.02; Figure 2a). When the rs10916264:TP53 interaction model was calculated separately for each study, all studies were in agreement on the direction of the interaction term (I2 = 11.72%, Q test for heterogeneity p = 0.3927; Figure 3). The interaction remained statistically significant (p = 2.6 × 10-4) when adjuvant endocrine therapy was included in the Cox model, and the interaction exists at a nominally significant level even among ER-positive cases not treated with endocrine therapy (n = 843, 140 events, p = 0.04). The interaction was also independent of adjuvant chemotherapy treatment with nominally significant interaction p-values in both chemotherapy-treated and untreated groups (p = 0.033 and 0.028, respectively).

View Article: PubMed Central - PubMed

ABSTRACT

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.

In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 05E010-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 05E010-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.

If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

No MeSH data available.