Identification of genes associated with multiple cancers via integrative analysis

<p>Abstract</p> <p>Background</p> <p>Advancement in gene profiling techniques makes it possible to measure expressions of thousands of genes and identify genes associated with development and progression of cancer. The identified cancer-associated genes can be used for diagnosis, prognosis prediction, and treatment selection. Most existing cancer microarray studies have been focusing on the identification of genes associated with a specific type of cancer. Recent biomedical studies suggest that different cancers may share common susceptibility genes. A comprehensive description of the associations between genes and cancers requires identification of not only multiple genes associated with a specific type of cancer but also genes associated with multiple cancers.</p> <p>Results</p> <p>In this article, we propose the Mc.TGD (Multi-cancer Threshold Gradient Descent), an integrative analysis approach capable of analyzing multiple microarray studies on different cancers. The Mc.TGD is the first regularized approach to conduct "two-dimensional" selection of genes with joint effects on cancer development. Simulation studies show that the Mc.TGD can more accurately identify genes associated with multiple cancers than meta analysis based on "one-dimensional" methods. As a byproduct, identification accuracy of genes associated with only one type of cancer may also be improved. We use the Mc.TGD to analyze seven microarray studies investigating development of seven different types of cancers. We identify one gene associated with six types of cancers and four genes associated with five types of cancers. In addition, we also identify 11, 9, 18, and 17 genes associated with 4 to 1 types of cancers, respectively. We evaluate prediction performance using a Leave-One-Out cross validation approach and find that only 4 (out of 570) subjects cannot be properly predicted.</p> <p>Conclusion</p> <p>The Mc.TGD can identify a short list of genes associated with one or multiple types of cancers. The identified genes are considerably different from those identified using meta analysis or analysis of marginal effects.</p

Using Nodal Ratios to Predict Risk of Regional Recurrences in Patients Treated with Breast Conservation Therapy with 4 or More Positive Lymph Nodes

Purpose. The value of nodal ratios (NRs) as a prognostic variable in breast cancer is continually being demonstrated. The purpose of this study was to use NR in patients with ≥4+ nodes to assess a correlation of NR with regional (lymph node) recurrence. Methods. Inclusion criteria was ≥8 nodes dissected with ≥4+ nodes after breast conservation therapy. Of 1060 patients treated from 1975 to 2003 who had a minimum of 8 nodes dissected, 273 were node+; 56 patients had ≥4+ involved nodes and were the focus of this study. Nodal ratios were calculated for each patient and grouped into 3 categories: high (≥70%), intermediate (40%–69%) and low (<40%). Each nodal ratio was correlated with patterns of local, regional, and distant failures and OS. Results. Outcomes for the entire cohort were BRFS-83%, NRFS-93%, DMFS-61%, and OS 63% at 10 yrs. The OS, DMFS, and NRFS correlated with N2 (4–9 nodes+) versus N3 (≥10+) status but did not correlate with BRFS, as expected. When evaluating NR, 18 pts had high NR (>70%). Only 3 patients experienced nodal recurrences, all within previously radiated supraclavicular fields. All 3 in-field regional failures occurred in the N3 group of patients with NR >70%. All were treated with a single AP field prescribed to a dose of 46 Gy at a standard depth of 3 cm. Conclusions. In this group of N2/N3 patients treated with BCT, we were able to identify patients at high risk for regional failures as those with high NR of >70% and ≥10+ nodes. While these findings need to be reproduced in larger datasets, this group of patients with NR of >70% in 4 or more positive axillary lymph nodes may benefit from meticulous targeting of regional nodes, dose escalation, and/or more intensive systemic therapies

Identification of Novel Variants of Metadherin in Breast Cancer

Metadherin (MTDH, also known as AEG-1, and Lyric) has been demonstrated to play a potential role in several significant aspects of tumor progression. It has been reported that overexpression of MTDH is associated with progression of disease and poorer prognosis in breast cancer. However, there are no studies to date assessing variants of the MTDH gene and their potential relationship with breast cancer susceptibility. Thus, we investigated all variants of the MTDH gene and explored the association of the variants with breast cancer development. Our cohort consisted of full-length gene sequencing of 108 breast cancer cases and 100 healthy controls; variants were detected in 11 breast cancer cases and 13 controls. Among the variants detected, 9 novel variants were discovered and 2 were found to be associated with the susceptibility of breast cancer. However, additional studies need to be conducted in larger sample sizes to validate these findings and to further investigate whether these variants are prognostic in breast cancer patients

Is Proton Therapy a “Pro” for Breast Cancer? A Comparison of Proton vs. Non-proton Radiotherapy Using the National Cancer Database

Background: Limited data exists demonstrating the clinical benefit of proton radiotherapy (PRT) in breast cancer. Using the National Cancer Database, we evaluated predictors associated with PRT use for patients with breast cancer. An exploratory analysis also investigates the impact of PRT on overall survival (OS).Methods: Patients with non-metastatic breast cancer treated with adjuvant radiotherapy from 2004 to 2014 were identified. Patients were stratified based on receipt of PRT or non-PRT (i.e., photons ± electrons). A logistic regression model was used to determine predictors for PRT utilization. For OS, Multivariable analysis (MVA) was performed using Cox proportional hazard model.Results: A total of 724,492 patients were identified: 871 received PRT and 723,621 received non-PRT. 58.3% of the PRT patients were group stage 0–1. Median follow-up time was 62.2 months. On multivariate logistic analysis, the following factors were found to be significant for receipt of PRT (all p &lt; 0.05): academic facility (odds ratio [OR] = 2.50), South (OR = 2.01) and West location (OR = 12.43), left-sided (OR = 1.21), ER-positive (OR = 1.59), and mastectomy (OR = 1.47); pT2-T4 disease predicted for decrease use (OR = 0.79). PRT was not associated with OS on MVA for all patients: Hazard Ratio: 0.85, p = 0.168. PRT remained not significant on MVA after stratifying for subsets likely associated with higher heart radiation doses, including: left-sided (p = 0.140), inner-quadrant (p = 0.173), mastectomy (p = 0.095), node positivity (p = 0.680), N2-N3 disease (p = 0.880), and lymph node irradiation (LNI) (p = 0.767).Conclusions: Receipt of PRT was associated with left-sided, ER+ tumors, mastectomy, South and West location, and academic facilities, but not higher group stages or LNI. PRT was not associated with OS, including in subsets likely at risk for higher heart doses. Further studies are required to determine non-OS benefits of PRT. In the interim, given the high cost of protons, only well-selected patients should receive PRT unless enrolled on a clinical trial

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum