| 1. |
- Nemes, Szilard, 1977, et al.
(författare)
-
A diagnostic algorithm to identify paired tumors with clonal origin.
- 2013
-
Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 52:11, s. 1007-16
-
Tidskriftsartikel (refereegranskat)abstract
- Despite practical implications we still lack standardized methods for clonality testing of tumor pairs. Each tumor is characterized by a set of chromosomal abnormalities, nonrandom changes preferentially involving specific chromosomes and chromosomal regions. Although tumors accumulate chromosomal abnormalities during their development, the majority of these alterations is specific and characteristic for each individual tumor is not exhibited at the population level. Assumingly, secondary tumors that develop from disseminated cells from the primary tumor inherit not only chromosomal changes specific for the cancerous process but also random chromosomal changes that accumulate during tumor development. Based on this assumption, we adopted an intuitive index for genomic similarities of paired tumors, which ranges between zero (completely different genomic profiles) and one (identical genomic profiles). To test the assumption that two tumors have clonal origins if they share a higher degree of genomic similarity than two randomly paired tumors, we built a permutation-based null-hypothesis procedure. The procedure is demonstrated using two publicly available data sets. The article highlights the complexities of clonality testing and aims to offer an easy to follow blueprint that will allow researchers to test genomic similarities of paired tumors, with the proposed index or any other index that fits their need. © 2013 Wiley Periodicals, Inc.
|
|
| 2. |
- Nemes, Szilard, 1977, et al.
(författare)
-
Integrative genomics with mediation analysis in a survival context
- 2013
-
Ingår i: Computational and mathematical methods in medicine. - : Hindawi Limited. - 1748-6718 .- 1748-670X. ; 2013, s. 413783-
-
Tidskriftsartikel (refereegranskat)abstract
- DNA copy number aberrations (DCNA) and subsequent altered gene expression profiles may have a major impact on tumor initiation, on development, and eventually on recurrence and cancer-specific mortality. However, most methods employed in integrative genomic analysis of the two biological levels, DNA and RNA, do not consider survival time. In the present note, we propose the adoption of a survival analysis-based framework for the integrative analysis of DCNA and mRNA levels to reveal their implication on patient clinical outcome with the prerequisite that the effect of DCNA on survival is mediated by mRNA levels. The specific aim of the paper is to offer a feasible framework to test the DCNA-mRNA-survival pathway. We provide statistical inference algorithms for mediation based on asymptotic results. Furthermore, we illustrate the applicability of the method in an integrative genomic analysis setting by using a breast cancer data set consisting of 141 invasive breast tumors. In addition, we provide implementation in R.
|
|
| 3. |
- Nemes, Szilard, 1977, et al.
(författare)
-
Segmented regression, a versatile tool to analyze mRNA levels in relation to DNA copy number aberrations.
- 2012
-
Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 51:1, s. 77-82
-
Tidskriftsartikel (refereegranskat)abstract
- DNA copy number aberrations (CNA) and subsequent altered gene expression profiles (mRNA levels) are characteristic features of cancerous cells. Integrative genomic analysis aims to identify recurrent CNA that may have a potential role in cancer development, assuming that gene amplification is accompanied by overexpression, while deletions give rise to downregulation of gene expression. We propose a segmented regression-based approach to identify CNA-driven alteration of gene expression profiles. Segmented regression allows to fit piecewise linear models in different domains of CNA joined by a change-point, where the mRNA-CNA relationship undergoes structural changes. Here, we illustrate the implementation and applicability of the proposed model using 1,161 chromosome fragments detected as DNA CNA in primary tumors from 97 breast cancer patients. We identified significant CNA-driven changes in gene expression levels for 341 chromosome fragments, of which 72 showed a nonlinear relationship to CNA. For 59 of 72 chromosome fragments (82%), we observed an initial increase in mRNA levels due to changes in CNA. After the change-point was passed, the mRNA levels reached a plateau, and a further increase in DNA copy numbers did not induce further elevation in mRNA levels. In contrast, for 13 chromosome fragments, the change-point marked the point where mRNA production accelerated. We conclude that segmented regression modeling may provide valuable insights into the impact CNA have on gene expression in cancer cells. © 2011 Wiley Periodicals, Inc.
|
|
