Genotype and Haplotype Analyses of <i>TP53</i> Gene in Breast Cancer Patients: Association with Risk and Clinical Outcomes

<div><p>Variations in the <i>TP53</i> gene have been suggested to play a role in many cancers, including breast. We previously observed an association between <i>TP53</i> haplotypes based on four polymorphisms (rs17878362, rs1042522, rs12947788, and rs17884306) and the risk of colorectal and pancreatic cancer. Based on these results, in the present study, we have investigated the same polymorphisms and their haplotypes in 705 breast cancer cases and 611 healthy controls in relation to the disease risk, histopathological features of the tumor and clinical outcomes. In comparison to the most common haplotype A₁-G-C-G, all the other identified haplotypes were globally associated with a significantly decreased breast cancer risk (P = 0.006). In particular, the A₂-G-C-G haplotype was associated with a marked decreased risk of breast cancer when compared with the common haplotype (P = 0.0001). Moreover, rs1042522 in patients carrying the GC genotype and receiving only the anthracycline-based chemotherapy was associated with both overall and disease-free survival (recessive model for overall survival HR = 0.30 95% CI 0.11–0.80, P = 0.02 and for disease-free survival HR = 0.42 95% CI 0.21–0.84, P = 0.01). Present results suggest common genetic features in the susceptibility to breast and gastrointestinal cancers in respect to <i>TP53</i> variations. In fact, similar haplotype distributions were observed for breast, colorectal, and pancreatic patients in associations with cancer risk. Rs1042522 polymorphism (even after applying the Dunn-Bonferroni correction for multiple testing) appears to be an independent prognostic marker in breast cancer patients.</p></div

Kaplan-Meier disease-free survival curves for <i>TP53</i> rs17878362 polymorphism in patients receiving only the hormonal therapy (log-rank for recessive model).

<p>Numbers of patients at risk are indicated in the lower part of the plot.</p

OS and DFS in relation to haplotype distributions (Cox regression).

<p>^aLoci rs17878362, rs1042522, rs12947788, rs17884306.</p><p>^b Number of alleles are reported. Because each individual has two alleles, the total number of alleles is twice the total number of individuals. Individuals with missing haplotype data were not included in the analyses.</p><p>^cAllele A₂ carries the 16-bp insertion within intron 3</p><p>HR, hazard ratio; 95% CI, confidence interval. Significant results in bold.</p><p>OS and DFS in relation to haplotype distributions (Cox regression).</p

<i>TP53</i> haplotype distribution between BC patients and controls.

<p>^aLoci rs17878362, rs1042522, rs12947788, rs17884306.</p><p>^bNumber of alleles are reported. Because each individual has two alleles, the total number of alleles will be twice the total number of individuals. Individuals with missing haplotype data were not included in the analyses.</p><p>^cAdjusted for age.</p><p>^dAllele A₂ carries the 16-bp insertion within intron 3</p><p>OR, odds ratio; CI, confidence interval. Significant P-values are in bold.</p><p><i>TP53</i> haplotype distribution between BC patients and controls.</p

Overall (OS) and disease-free (DFS) survival in relation to SNP distributions (Cox regression).

<p>The SNP rs17884306 was monomorphic in cases, thus not presented.</p><p>HR, hazard ratio; 95% CI, confidence interval. Significant results in bold.</p><p>Overall (OS) and disease-free (DFS) survival in relation to SNP distributions (Cox regression).</p

OS and DFS in relation to SNP distributions in patients treated with anthracycline-based chemotherapy (Cox regression).

<p>The SNP rs17884306 was monomorphic in cases, thus not presented.</p><p>HR, hazard ratio; 95% CI, confidence interval. Significant results in bold; significant differences after Dunn–Bonferroni correction (P<0.02) are marked with an asterisk.</p><p>OS and DFS in relation to SNP distributions in patients treated with anthracycline-based chemotherapy (Cox regression).</p

Estrogen Receptor Status Oppositely Modifies Breast Cancer Prognosis in <i>BRCA1/BRCA2</i> Mutation Carriers Versus Non-Carriers

Breast cancer (BC) prognosis in BRCA1 and BRCA2 mutation carriers has been reported contradictorily, and the significance of variables influencing prognosis in sporadic BC is not established in BC patients with hereditary BRCA1/BRCA2 mutations. In this retrospective cohort study, we analyzed the effect of clinicopathological characteristics on BC prognosis (disease-free survival [DFS] and disease-specific survival [DSS]) in hereditary BRCA1/BRCA2 mutation carriers. We enrolled 234 BRCA1/BRCA2 mutation carriers and 899 non-carriers, of whom 191 carriers and 680 non-carriers, with complete data, were available for survival analyses. We found that patients with ER-positive tumors developed disease recurrence 2.3-times more likely when they carried a BRCA1/BRCA2 mutation (23/60; 38.3% ER-positive carriers vs. 74/445; 16.6% ER-positive non-carriers; p &lt; 0.001). ER-positive mutation carriers also had a 3.4-times higher risk of death due to BC compared with ER-positive non-carriers (13/60; 21.7% vs. 28/445; 6.3%; p &lt; 0.001). Moreover, prognosis in ER-negative BRCA1/BRCA2 mutation carriers was comparable with that in ER-positive non-carriers. Our study demonstrates that ER-positivity worsens BC prognosis in BRCA1/BRCA2 mutation carriers, while prognosis for carriers with ER-negative tumors (including early-onset) is significantly better and comparable with that in ER-positive, older BC non-carriers. These observations indicate that BRCA1/BRCA2 mutation carriers with ER-positive BC represent high-risk patients