Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium

Association studies in large series of breast cancer patients can be used to identify single-nucleotide polymorphisms (SNP) contributing to breast cancer susceptibility. Previous studies have suggested associations between variants in TP53 (R72P) and MDM2 (SNP309) and cancer risk. Data from molecular studies suggest a functional interaction between these genes. We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer risk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium (BCAC). Breast cancer risk was not found to be associated with the combined variant alleles [odds ratio (OR), 1.00; 95% confidence interval (95% CI), 0.81-1.23]. Estimated ORs were 1.01 (95% CI, 0.93-1.09) per MDM2 SNP309 allele and 0.98 (95% CI, 0.91-1.04) for TP53 R72P. Although we did find evidence for a 4-year earlier age at onset for carriers of both variant alleles in one of the breast cancer patient series of the BCAC (the German series), we were not able to confirm this effect in the pooled analysis. Even so, carriers of both variant alleles did not have different risk estimates for bilateral or estrogen receptor-positive breast cancer. In conclusion, in this large collaborative study, we did not find an association of MDM2 SNP309 and TP53 R72P, separately or in interaction, with breast cancer. This suggests that any effect of these two variants would be very small and possibly confined to subgroups that were not assessed in our present study.     

Role of IL-12p40 in cervical carcinoma

Background:

Previously, we have shown that low IL-12p40 mRNA expression by cervical cancer cells is associated with a poor survival of cervical cancer patients. As IL-12p40 is both a subcomponent of interleukin (IL)-12 and IL-23, the aim of this study was to elucidate the role of IL-12p40 in cervical cancer.

Methods:

We have measured the expression of IL-23p19 mRNA, IL-12p35 mRNA and IL-12p40 mRNA using mRNA in situ hybridisation. The IL-1 and IL-6 were measured by immunohistochemistry.

Results:

As IL-23 is a component of the IL-17/IL-23 pathway, a pathway induced by IL-1 and IL-6 in humans, we have studied IL-1 and IL-6 expression. Only a high number of stromal IL-6-positive cells was shown to associate with poor disease-specific survival. The worst disease-specific survival was associated with a subgroup of patients that displayed a high number of IL-6-positive cells and low IL-12p40 expression (P<0.001). Both a high number of IL-6-positive cells and a high number of IL-6-positive cells, plus low IL-12p40 expression were shown to be clinicopathological parameters independent of lymph node metastasis, parametrial involvement and Sedlis score (P=0.009 and P=0.007, respectively).

Conclusion:

Our results with IL-6 and IL-12p40 are in accordance with the hypothesis that the IL-17/IL-23 pathway has a suppressive role in cervical cancer.     

Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine.

PURPOSE: The study aims to evaluate the effect of a human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides vaccine on the antigen-specific T-cell response in cervical cancer patients. EXPERIMENTAL DESIGN: Patients with resected HPV16-positive cervical cancer were vaccinated with an overlapping set of long peptides comprising the sequences of the HPV16 E6 and E7 oncoproteins emulsified in Montanide ISA-51. HPV16-specific T-cell immune responses were analyzed by evaluating the magnitude, breadth, type, and polarization by proliferation assays, IFN gamma-ELISPOT, and cytokine production and phenotyped by the T-cell markers CD4, CD8, CD25, and Foxp3. RESULTS: Vaccine-induced T-cell responses against HPV16 E6 and E7 were detected in six of six and five of six patients, respectively. These responses were broad, involved both CD4(+) and CD8(+) T cells, and could be detected up to 12 months after the last vaccination. The vaccine-induced responses were dominated by effector type CD4(+)CD25(+)Foxp3(-) type 1 cytokine IFN gamma-producing T cells but also included the expansion of T cells with a CD4(+)CD25(+)Foxp3(+) phenotype. CONCLUSIONS: The HPV16 E6 and E7 synthetic long peptides vaccine is highly immunogenic, in that it increases the number and activity of HPV16-specific CD4(+) and CD8(+) T cells to a broad array of epitopes in all patients. The expansion of CD4(+) and CD8(+) tumor-specific T cells, both considered to be important in the antitumor response, indicates the immunotherapeutic potential of this vaccine. Notably, part of the vaccine-induced T cells display a CD4(+)CD25(+)Foxp3(+) phenotype that is frequently associated with regulatory T-cell function, suggesting that strategies to disarm this subset of T cells should be considered as components of immunotherapeutic modalities against HPV-induced cancers.     

The number of pelvic lymph nodes in the quality control and prognosis of radical hysterectomy for the treatment of cervical cancer.

AIMS: To determine if the number of removed lymph nodes in radical hysterectomy with lymphadenectomy (RHL) influences survival of patients with early stage cervical cancer and to analyze the relation of different factors like patient age, tumour size and infiltration depth with the number of nodes examined in node-negative early stage cervical cancer patients. METHODS: Of consecutive patients, who underwent RHL between January 1984 and April 2005, 331 had negative nodes (group A) without adjuvant therapy and 136 had positive nodes (group B). The Kaplan-Meier method and Cox regression model were used to detect statistical significance. Factors associated with excision of nodes were confirmed with linear regression models. RESULTS: The median number of removed nodes was 19 and 18 for group A and group B, respectively. There was no significant relationship between the number of removed nodes and the cancer specific survival (CSS) or disease free survival (DSF) for patients of group A (p=0.625 and p=0.877, respectively). The number of removed nodes in group B was not significantly associated with the CSS (p=0.084) but it was for the DSF (p=0.014). Factors like patient age, tumour size and infiltration depth were not associated with the number of nodes. CONCLUSIONS: No relation was found between the number of negative nodes examined after RHL for the treatment of early stage cervical cancer and CSS or DFS. However, a higher amount of removed lymph nodes leaded to a better DFS for patients with positive nodes. It is suggested that patients with positive nodes benefit from a complete pelvic lymphadenectomy and a sufficient yield of removed nodes.     

Prognostic relevance of TGF-beta1 and PAI-1 in cervical cancer

Cervical carcinoma is a human papilloma virus (HPV)-related immunogenic type of malignancy, in which escape of the tumor from the hosts' immune response is thought to play an important role in carcinogenesis. The multifunctional cytokine transforming growth factor-beta(1) (TGF-beta(1)) is involved in immunosuppression, stroma and extracellular matrix formation and controlling (epithelial) cell growth. The plasminogen activating (PA) system plays a key role in the cascade of tumor-associated proteolysis leading to extracellular matrix degradation and stromal invasion. Changes in expression of components of this system, including plasminogen activator inhibitor-1 (PAI-1), have been associated with poor prognosis in a variety of solid tumors. The present study was undertaken to assess the role of both components on relapse, survival and other clinicopathologic parameters in cervical cancer. The expression of TGF-beta(1) mRNA in 108 paraffin-embedded cervical carcinomas was detected by mRNA in situ hybridization. Immunohistochemistry was used to investigate the expression of PAI-1 protein. The presence of cytoplasmatic TGF-beta(1) mRNA in tumor cells was not significantly correlated with the other clinicopathologic parameters investigated or with a worse (disease-free) survival. Expression of the PAI-1 protein in tumor cells was strongly correlated with worse overall and disease-free survival, in addition to well-known prognostic parameters such as lymph node metastasis, depth of tumor infiltration, tumor size and vasoinvasion. In the multivariate analysis, PAI-1 turned out to be a strong independent prognostic factor. In a subgroup of patients without lymph node metastases, PAI-1 was predictive for worse survival and relapse of disease, too. Our results show that the (enhanced) expression of PAI-1 by carcinoma cells is correlated with worse (overall and disease-free) survival of patients with cancer of the uterine cervix. The expression of TGF-beta(1) in itself is not associated with worse survival in these patients. Although simultaneous presence of the 2 factors was observed in all tumors, induction of PAI-1 by TGF-beta(1) could not be demonstrated in our group of cervical carcinomas.     

Excess Risk for Contralateral Breast Cancer in CHEK2*1100delC Germline Mutation Carriers

We detected a significant excess risk for CHEK2*1100delC mutation carriers to develop a contralateral breast tumor, OR = 6.5 (95% CI 1.5-28.8, p = 0.005). The highest percentage of mutation carriers was detected among those bilateral breast cancer patients who had received radiation treatment for their first breast tumor. These results warrant prolonged medical surveillance and may indicate a clinically important interaction between CHEK2 heterozygosity and radiation in the development of contralateral breast cancer.     

Tumor diameter and volume assessed by magnetic resonance imaging in the prediction of outcome for invasive cervical cancer

OBJECTIVE: The aim of this study was to evaluate the predictive value of pretherapeutic magnetic resonance imaging (MRI)-based measurements of tumor diameter and volume with regard to recurrent disease. METHODS: MRI on 0.5- or 1.5-T scanners was performed in 126 consecutive women with invasive carcinoma of the uterine cervix. Initial tumor diameter and volume were determined on T(2)-weighted images; volume was calculated by the standard technique of multiplying the sum of the areas by the slice thickness. Patients were treated by radical surgery, radiotherapy, or a combined approach based on clinical International Federation of Gynecology and Obstetrics (FIGO) stage and individual patient criteria. Clinical data (patient age and FIGO stage), MRI-derived tumor dimensions (diameter and volume), and histological findings (tumor invasion depth and lymph-node involvement) were associated and linked to patient outcome. RESULTS: MRI-based tumor diameter correlated strongly with histological tumor invasion depth and lymph-node status (P < 0.01 and P = 0.01) while tumor volume on MRI was significantly associated only with tumor invasion depth into adjacent tissues (P < 0.01). Univariate analysis demonstrated graphically that MRI-derived tumor diameter and volume and clinical FIGO stage are associated with progression-free survival. Correlation analysis showed a strong association between MRI-derived tumor diameter and volume on MRI (r = 68%, P < 0.01) and also demonstrated a correlation between tumor diameter on MRI and FIGO stage Ib (Ib1 versus Ib2) cervical tumors (r = 46.7%, P < 0.01). CONCLUSION: Tumor diameter and volume, determined by pretreatment MRI examinations, predict progression-free survival for patients with invasive cervical carcinoma. This study demonstrates the value of MRI as an adjunct to clinical evaluation of invasive cervical cancer, providing more complete assessment of morphological risk factors important in patient prognosis and treatment planning.