Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Longitudinal Determinants of Consistent Condom Use by Partner Type Among Young Injection Drug Users: The Role of Personal and Partner Characteristics

We investigated the longitudinal influence of individual-, relationship- and social-level factors on condom use by partner type among young injections drug users (IDUs) enrolled in the Collaborative Injection Drug Users Study-III/Drug Users Intervention Trial (CIDUS-III/DUIT) from 2002 to 2004. Based on longitudinal analysis using generalized estimating equations (GEE), consistent condom use with main partners was more commonly reported among males and those with greater self-efficacy for condom use; main partner’s desire for pregnancy and needle sharing were negatively associated with consistent condom use. Among those with casual partners, having fewer sex partners was associated with consistent condom use. Positive attitudes toward condom use and partner norms supporting condom use were associated with greater consistent condom use with both partner types. These findings suggest that intervention strategies targeting individual- and partner-level factors may provide avenues for intervening upon sexual risks among young IDUs

Late HIV Diagnosis and Determinants of Progression to AIDS or Death after HIV Diagnosis among Injection Drug Users, 33 US States, 1996–2004

BACKGROUND: The timeliness of HIV diagnosis and the initiation of antiretroviral treatment are major determinants of survival for HIV-infected people. Injection drug users (IDUs) are less likely than persons in other transmission categories to seek early HIV counseling, testing, and treatment. Our objective was to estimate the proportion of IDUs with a late HIV diagnosis (AIDS diagnosis within 12 months of HIV diagnosis) and determine the factors associated with disease progression after HIV diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: Using data from 33 states with confidential name-based HIV reporting, we determined the proportion of IDUs aged >or=13 years who received a late HIV diagnosis during 1996-2004. We used standardized Kaplan-Meier survival methods to determine differences in time of progression from HIV to AIDS and death, by race/ethnicity, sex, age group, CD4(+) T-cell count, metropolitan residence, and diagnosis year. We compared the survival of IDUs with the survival of persons in other transmission categories. During 1996-2004, 42.2% (11,635) of 27,572 IDUs were diagnosed late. For IDUs, the risk for progression from HIV to AIDS 3 years after HIV diagnosis was greater for nonwhites, males and older persons. Three-year survival after HIV diagnosis was lower for IDU males (87.3%, 95% confidence interval (CI), 87.1-87.4) compared with males exposed through male-to-male sexual contact (91.6%, 95% CI, 91.6-91.7) and males exposed through high-risk heterosexual contact (HRHC) (91.9%, 95% CI, 91.8-91.9). Survival was also lower for IDU females (89.5%, 95% CI, 89.4-89.6) compared to HRHC females (93.3%, 95% CI, 93.3-93.4). CONCLUSIONS/SIGNIFICANCE: A substantial proportion of IDUs living with HIV received their HIV diagnosis late. To improve survival of IDUs, HIV prevention efforts must ensure early access to HIV testing and care, as well as encourage adherence to antiretroviral treatment to slow disease progression

Association between expatriation and HIV awareness and knowledge among injecting drug users in Kabul, Afghanistan: A cross-sectional comparison of former refugees to those remaining during conflict

BACKGROUND: Little is known about human immunodeficiency virus (HIV) awareness among Afghan injecting drug users (IDUs), many of whom initiated injecting as refugees. We explored whether differences in HIV awareness and knowledge exist between Afghan IDUs who were refugees compared to those never having left Afghanistan. METHODS: A convenience sample of IDUs in Kabul, Afghanistan was recruited into a cross-sectional study through street outreach over a one year period beginning in 2005. Participants completed an interviewer-administered questionnaire and underwent voluntary counseling and testing for HIV, syphilis, hepatitis B surface antigen, and hepatitis C antibody. Differences in HIV awareness and specific HIV knowledge between IDU who lived outside the country in the last decade versus those who had not were assessed with logistic regression. RESULTS: Of 464 IDUs, 463 (99%) were male; median age and age at first injection were 29 and 25 years, respectively. Most (86.4%) had lived or worked outside the country in the past ten years. Awareness of HIV was reported by 46.1%; those having been outside the country in the last decade were significantly more likely to have heard of HIV (48.3% vs. 31.7%; OR = 2.00, 95% CI: 1.14 – 3.53). However, of those aware of HIV, only 38.3% could name three correct transmission routes; specific HIV knowledge was not significantly associated with residence outside the country. CONCLUSION: Accurate HIV knowledge among Afghan IDUs is low, though former refugees had greater HIV awareness. Reported high-risk injecting behavior was not significantly different between IDU that were refugees and those that did not leave the country, indicating that all Afghan IDU should receive targeted prevention programming

Fanconi anemia genes are highly expressed in primitive CD34(+ )hematopoietic cells

BACKGROUND: Fanconi anemia (FA) is a complex recessive genetic disease characterized by progressive bone marrow failure (BM) and a predisposition to cancer. We have previously shown using the Fancc mouse model that the progressive BM failure results from a hematopoietic stem cell defect suggesting that function of the FA genes may reside in primitive hematopoietic stem cells. METHODS: Since genes involved in stem cell differentiation and/or maintenance are usually regulated at the transcription level, we used a semiquantitative RT-PCR method to evaluate FA gene transcript levels in purified hematopoietic stem cells. RESULTS: We show that most FA genes are highly expressed in primitive CD34-positive and negative cells compared to lower levels in more differentiated cells. However, in CD34(- )stem cells the Fancc gene was found to be expressed at low levels while Fancg was undetectable in this population. Furthermore, Fancg expression is significantly decreased in Fancc -/- stem cells as compared to wild-type cells while the cancer susceptibility genes Brca1 and Fancd1/Brac2 are upregulated in Fancc-/- hematopoietic cells. CONCLUSIONS: These results suggest that FA genes are regulated at the mRNA level, that increased Fancc expression in LTS-CD34(+ )cells correlates with a role at the CD34(+ )differentiation stage and that lack of Fancc affects the expression of other FA gene, more specifically Fancg and Fancd1/Brca2, through an unknown mechanism

Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer

Fanconi anemia (FA) is a recessive disorder associated with progressive pancytopenia, multiple developmental defects, and marked predisposition to malignancies. FA is genetically heterogeneous, comprising at least 12 complementation groups (A–M). Activation of one of the FA proteins (FANCD2) by mono-ubiquitination is an essential step in DNA damage response. As FANCD2 interacts with BRCA1, is expressed in proliferating normal breast cells, and FANCD2 knockout mice develop breast tumors, we investigated the expression of FANCD2 in sporadic and hereditary invasive breast cancer patients to evaluate its possible role in breast carcinogenesis. Two tissue microarrays of 129 and 220 sporadic breast cancers and a tissue microarray containing 25 BRCA1 germline mutation-related invasive breast cancers were stained for FANCD2. Expression results were compared with several clinicopathological variables and tested for prognostic value. Eighteen of 96 (19%) sporadic breast cancers and two of 21 (10%) BRCA1-related breast cancers were completely FANCD2-negative, which, however, still showed proliferation. In the remaining cases, the percentage of FANCD2-expressing cells correlated strongly with mitotic index and percentage of cells positive for the proliferation markers Ki-67 and Cyclin A. In immunofluorescence double staining, coexpression of FANCD2 and Ki-67 was apparent. In survival analysis, high FANCD2 expression appeared to be prognostically unfavorable for overall survival (p = 0.03), independent from other major prognosticators (p = 0.026). In conclusion, FANCD2 expression is absent in 10–20% of sporadic and BRCA1-related breast cancers, indicating that somatic inactivating (epi)genetic events in FANCD2 may be important in both sporadic and hereditary breast carcinogenesis. FANCD2 is of independent prognostic value in sporadic breast cancer

Array-based DNA methylation profiling of primary lymphomas of the central nervous system

<p>Abstract</p> <p>Background</p> <p>Although primary lymphomas of the central nervous system (PCNSL) and extracerebral diffuse large B-cell lymphoma (DLBCL) cannot be distinguished histologically, it is still a matter of debate whether PCNSL differ from systemic DLBCL with respect to their molecular features and pathogenesis. Analysis of the DNA methylation pattern might provide further data distinguishing these entities at a molecular level.</p> <p>Methods</p> <p>Using an array-based technology we have assessed the DNA methylation status of 1,505 individual CpG loci in five PCNSL and compared the results to DNA methylation profiles of 49 DLBCL and ten hematopoietic controls.</p> <p>Results</p> <p>We identified 194 genes differentially methylated between PCNSL and normal controls. Interestingly, Polycomb target genes and genes with promoters showing a high CpG content were significantly enriched in the group of genes hypermethylated in PCNSL. However, PCNSL and systemic DLBCL did not differ in their methylation pattern.</p> <p>Conclusions</p> <p>Based on the data presented here, PCNSL and DLBCL do not differ in their DNA methylation pattern. Thus, DNA methylation analysis does not support a separation of PCNSL and DLBCL into individual entities. However, PCNSL and DLBCL differ in their DNA methylation pattern from non- malignant controls.</p

The context and potential of epigenetics in oncology

Cancer has long been known to be a disease caused by alterations in the genetic blueprint of cells. In the past decade it has become evident that epigenetic processes have a function, at least equally important, in neoplasia. Epigenetics describes the mechanisms that result in heritable alterations in gene expression profiles without an accompanying change in DNA sequence. Genetics and epigenetics intricately interact in the pathogenesis of cancer (Esteller, 2007). In this review, we paint a broad picture of current understanding of epigenetic changes in cancer cells and reflect on the immense clinical potential of emerging knowledge of epigenetics in the diagnosis, prognostic assessment, treatment, and screening of cancer