Current Cancer Therapy Reviews - Volume 10, Issue 2, 2014

Clonal heterogeneity and clonal evolution have emerged as critical concepts in the field of oncology over the past four decades, largely thanks to the implementation of novel technologies such as comparative genomic hybridization, whole genome/exome sequencing and epigenetic analysis. Along with the identification of cancer stem cells in the majority of neoplasia, the recognition of intertumor and intratumor variability has provided a novel perspective to understand the mechanisms behind tumor evolution and its implication in terms of treatment failure and cancer relapse or recurrence. First hypothesized over two decades ago, clonal heterogeneity and clonal evolution have been confirmed in multiple myeloma (MM), an incurable cancer of plasma cells, almost universally preceded by a pre-malignant conditioned named monoclonal gammopathy of undetermined significance (MGUS). The genetic events and molecular mechanisms underlying such evolution have been difficult to dissect. Moreover, while a role for the bone marrow microenvironment in supporting MM cell survival, proliferation and drug-resistance has been well established, whether it is directly involved in driving evolution from MGUS to MM is at present unclear. We present in this review a historical excursus on the concepts of clonal heterogeneity and clonal evolution in MM with a special emphasis on their role in the progression from MGUS to MM; the contribution of the microenvironment; and the clinical implications in terms of resistance to treatment and disease relapse/recurrence.

Composite lymphomas (CLs) are characterized by the rare occurrence of two or more morphologically and/or immunophenotypically different lymphomas in the same anatomic tissue site. Many different combinations of lymphoma have been reported including multiple B-cell lymphomas, B-cell and T-cell non Hodgkin lymphomas, non Hodgkin lymphomas and Hodgkin lymphoma and complex B-cell, T-cell and Hodgkin lymphoma cases. The two lymphoma components usually are not clonally related but the use of thorough molecular techniques revealed that in some cases the two components are clonally related suggesting origin from a common progenitor cell. Pathogenesis of these lymphomas remains not well defined and the etiology differs according to the types of lymphomas involved. Composite B-cell lymphomas with two distinct low grade components are rare and usually are characterized by the existence of two different unrelated progenitors. CLs consisting of two types of non Hodgkin lymphomas of the same lineage, mostly B-cells, represent in most of the cases tumor progression and transformation from an indolent B-cell lymphoma to diffuse large B-cell lymphoma (DLBCL) and the low grade and high grade components in this type of CL are often clonally related while a clonal link has also been reported in cases of CLs containing Hodgkin lymphoma with various non Hodgkin lymphomas. CLs must be carefully diagnosed because the containing disease entities may not only have different natural course but also may differ in prognosis and treatment.

We studied aberrant changes (A-IgC) in the production of monoclonal intact immunoglobulin (M-Ig) or serum free light chains (sFLC) during symptomatic MM patients’ relapse and we evaluated their frequency and the associated disease characteristics. Patients and Methods: 234 symptomatic MM patients, with available follow-up M-Ig and sFLC measurements, were retrospectively studied. Light chain escape (LCE) was defined as sFLC increase with stable or falling M-Ig, M-Ig escape (MCE) as decreasing sFLC with increasing M-Ig, de-differentiation (DD) as clinical relapse with normal or decreased MIg and sFLC and Clonal Domination (CD) as normalization of formerly increased IgG, IgA or FLC in relapsing patients presenting increase of another monoclonal component. Results: A-IgC was observed in 18% of patients, LCE in 8%, MCE in 3%, DD in 2% and CD in 5%; The median time from diagnosis to A-IgC was 48.5, 35.5, 31 and 46 months for LCE, MCE, DD and CD respectively. Median survival from A-IgC to last follow-up or death was 2.6, 3.3 and 6.3 months respectively for LCE, MCE and DD versus 31.1 months for CD patients (p=0.0002). Patients received a median of 3 treatment lines, including novel agents and/or ASCT, prior to A-IgC. In conclusion, LCE, MCE and DD are late events in the course of MM, observed in heavily pre-treated patients, associated with a very aggressive disease with shortened survival thereafter, probably due to the emergence of new resistant clones or to the dominance of pre-existing minor ones.

Cells in the stromal microenvironment facilitate colorectal cancer (CRC) progression and “co-evolve” with the epithelial cancer cells. Genetic and epigenetic differences between normal colorectal mucosa fibroblasts (NF) and carcinoma- associated fibroblasts (CAF) are not known. The aim of this study is to identify differentially expressed genes and promoter methylation between NF and CAF in human CRC. RNA and DNA were extracted from cultured NF and CAF from CRC resections. Genome-wide gene expression and methylation analyses were performed using the Illumina Human HT-12 v4.0 Expression and Illumina Human Methylation27 BeadChips. Gene expression values between NF and CAF were compared and correlated with methylation patterns. Data was analyzed with Partek Genomics Suite using one-way ANOVA and p<0.05 as significant. Ingenuity iReportTM was performed to identify potential differences in biological functions and pathways between the NF and CAF. Paired methylation and gene expression analyses from 11 NF and 10 CAF colorectal samples are reported. Unsupervised analysis of differentially expressed genes using iReportTM identified “Top Diseases” as “Cancer” and “Colorectal Cancer”. Previous genome wide studies have focused on the cancer cells. We have identified differentially expressed genes and differentially methylated promoter regions that are CAF-specific in CRC.