Association of HLA-G 3′UTR polymorphisms and haplotypes with colorectal cancer susceptibility and prognosis

Human leukocyte antigen (HLA)-G has been considered as an immune modulator in several types of cancers. Its genetic polymorphisms may potentially affect the risk of developing colorectal cancer (CRC). The overall purpose of this study was to analyze the implication of HLA-G 3′untranslated region (3′UTR) polymorphisms particularly 14 pb insertion/deletion (Ins/Del; rs371194629) and + 3142C/G (rs1063320) in CRC susceptibility and progression.A comparative analysis between patients (N = 233) and controls (N = 241) demonstrated that Del allele (Odds Ratios (OR) = 1.41, 95% CI = 1.091–1.819, p = 0.008), the homozygous Del/Del genotype (OR = 1.80, 95% CI = 1.205–2.664, p = 0.003) and the codominant C/G genotype (OR = 1.59, 95% CI = 1.106–2.272, p = 0.013) were associated to CRC risk. As expected, the DelG haplotype was associated with CRC susceptibility (OR = 1.47, 95% CI = 1.068–2.012, p = 0.018). Assessment of patients' survival by Kaplan-Meier analysis indicated that the Del allele and the homozygous Del/Del genotype were associated with reduced event free survival (EFS) (Respectively, p = 0.009 and p = 0.05). Interestingly, the Del allele and the homozygous Del/Del genotype have been revealed as independent prognostic factors for poor EFS in patients with CRC. Additionally, haplotypes analysis revealed that DelG haplotype was linked with significant increase in CRC risk (log-rank; EFS: p = 0.02). Inversely, the InsC haplotype was associated with a significant reduced CRC risk (log-rank; Overall survival (OS): p < 10^–6; EFS: p = 0.01). Multivariate Cox regression analysis revealed that the InsC haplotype was independently associated with significantly longer EFS (p = 0.021, HR = 0.636, 95% CI = 0.433–0.935).These findings support the implication of HLA-G polymorphisms in the CRC susceptibility suggesting HLA-G as a potent prognostic and predictive indicator for CRC. Insight into mechanisms underlying HLA-G polymorphisms could allow for the development of targeted care for CRC patients according to their genetic profile.     

Proximal 1q21 duplication: A syndrome or a susceptibility locus?

Proximal 1q21 microduplication is an incomplete penetrance and variable expressivity syndrome. This study reports 28 new cases and summarizes data on phenotype, gender, and parental origin. Data on isolated proximal 1q21.1 microduplications (g. chr1:145,394,956–145,762,959 GRCh37/hg19) was retrieved in postnatal and prenatal “clinical cases” group, and prenatal “control group.” The “clinical cases” cases included cases where chromosomal microarray (CMA) was performed due to congenital anomalies, autism spectrum disorder, seizures, and developmental delay/intellectual disability. The “control group” cases consisted of fetal CMA performed upon parental request despite normal nuchal translucency and anatomical second trimester fetal scans. We analyzed a local database of 27,990 cases and another cohort of 80,000 cases (including both indicated and non-indicated cases) for population frequency analysis. A total of 62 heterozygous cases were found, including 28 index cases and 34 family members. Among the index cases, 13 (9 males, 4 females) were identified in the “clinical cases” group, of which 10 had developmental abnormalities. Parental origin was tested in 9/13 cases, and all were found to be maternally inherited. In the “control group,” which comprised non-affected cases, of 15 cases (10 males, 5 females), only 5/11 were maternally inherited. Four cases with clinical follow-up showed no reported neurodevelopmental abnormalities. No de-novo cases were detected, and the population frequency in both cohorts was 1:1000. Proximal 1q21.1 microduplication is a recurrent copy number variant, associated with neurodevelopmental abnormalities. It has a greater impact on males inheriting it from their mothers than females from their fathers.     

Mesogastrium: A fifth route of metastasis in gastric cancer?

Radical gastrectomy for gastric cancer with D2 lymph node dissection has been widely applied in advanced gastric cancer. It is believed that such surgery should extremely sweep away local–regional tumor tissues and cancer cells and thoroughly prevent tumor recurrence in situ. However, for most patients with advanced gastric cancer, tumor local–regional recurrence has been proven unavoidable. This study has found that isolated cancer cells, separate from the primary lesion and lymph nodes, existed in the mesogastrium of resected gastric cancer specimens, leading to the hypothesis that these cancer cells may have infiltrated the mesogastrium through a fifth metastasis route (here named Metastasis V) which is distinct from the other four classic metastasis routes, and cannot be resected by conventional radical gastrectomy with D2 lymph node dissection. Local–regional recurrence might be closely associated with these cancer cells in the mesogastrium, and therefore, complete mesogastrium excision (CME) should be imperative and become the third radical principle for radical gastrectomy.     

Associations between vitamin D receptor polymorphisms and susceptibility to Behcet’s disease: A meta-analysis

Background: The vitamin D receptor (VDR) gene polymorphisms have been reported to be related to the development of Behcet’s disease (BD). However, the results have been inconsistent among diverse populations. Therefore, this comprehensive meta-analysis has been designed to assess a more accurate association between VDR polymorphisms and BD susceptibility.

Methods: An electronic literature search was conducted to identify eligible studies. Pooled odds ratios (OR) with corresponding 95% confidence interval (CI) were calculated in different genetic models to assess this association.

Results: A total of six separate comparisons comprised of 468 cases and 516 controls were included in the meta-analysis model. The meta-result demonstrated that A allele of ApaI (A vs. a: 1.54 95% CI = 1.04–2.26, P = 0.029), and F allele of FokI (F vs. f: OR = 0.58, 95% CI = 0.45–0.76, P = 0.007) polymorphisms were associated with the risk of BD in total and African populations, respectively. This significant association was also found in recessive and homozygotes models. Subgroup analysis indicated that FokI variant among Africans and ApaI variant among Caucasian were significantly associated with the risk of BD. No relationship was found between Bsmi and TaqI polymorphisms and BD risk.

Conclusion: This meta-analysis demonstrated the association between FokI and ApaI polymorphisms in VDR gene with the risk of BD, providing insights into the potential role of vitamin D receptor in the pathogenesis of BD.     

CYP 17 and estrogen receptor α gene polymorphisms: association with breast cancer susceptibility and clinicopathological parameters in a cohort of Egyptian patients

The association between exposure to endogenous and exogenous steroid hormones and breast cancer (BC) risk is well established. The aim of this study was to examine whether Cytochrome P450 (CYP)17 -34T>C and estrogen receptor (ER)α XbaI gene polymorphisms might influence endogenous estrogen hormone level. Also, we aimed to examine the potential association between these polymorphisms and BC risk, as well as some clinicopathological parameters in BC patients. Eighty-one Egyptian female subjects were recruited; 41 pathologically confirmed BC patients and 40 apparently healthy, age-matched female control subjects. Serum estradiol level was assayed using radioimmunoassay. Polymerase chain reaction–restriction fragment length polymorphism technique was used for detection of CYP 17 -34T>C and ERα-XbaI polymorphisms. Serum estradiol level did not show statistically significant difference when compared between the different CYP17 and ERα genotypes in controls (p?=?0.088 and 0.241, respectively). No significant association between CYP17 and ER α gene polymorphisms and BC risk was encountered. There was a statistically significant association between ER α genotypes in overall BC cases with each of age at menarche, p?=?0.024, age at diagnosis, p?=?0.011, and nodal involvement, p?=?0.037, and between nodal number and ER α genotypes in the premenopausal BC group, p?=?0.038. In conclusion, CYP17 and ERα genotypes did not influence serum estradiol level. No statistically significant association was found between CYP17 -34T>C and ERα XbaI gene polymorphisms and breast cancer risk in Egyptian women. ER α gene may have an association with some clinicopathological parameters in breast cancer in Egyptian patients.     

Erythropoietin in cancer: presumption of innocence?

Erythropoietin emerged as the biggest drug in oncology despite never having demonstrated a survival benefit in patients with cancer. Two phase III clinical trials reported more than 3 years ago that erythropoietin adversely affected cancer survival rates, due mainly to tumor progression. Despite changes to the product label for erythropoietins in 2004, clinical practice remained unchanged until recent weeks when, following reports of three new phase III studies and a phase II trial, a "black box warning" for erythropoietin products was issued by the Food and Drug Administration (FDA). Whether erythropoietin products can be considered safe when used for FDA-approved indications is currently at issue; however, addressing this question will be difficult until the mechanisms of erythropoietin-stimulated tumor progression are understood. A thorough evaluation of materials from clinical trials already completed may shed new light on how erythropoietin promotes cancer progression. Until these issues are resolved, oncologists should inform their patients of erythropoietin's potential adverse impact on cancer progression and survival. Disclosure of potential conflicts of interest is found at the end of this article.     

The measurement of cardiac markers: where should we focus?

Cardiac markers are presently a hot topic, with active debate on their use. They now have a major role for cost-effective management of acute chest pain and suspected acute coronary syndrome. The laboratory has a pivotal role in proper selection and interpretation of available markers, depending on the creation of evidence-based knowledge about test utilization and sources of variation. This article reviews this knowledge in the field of biomarkers determination and summarizes the major analytic and clinical issues, with reference to various recent recommendations of laboratory medicine and cardiology expert groups.     

Analysis of genetic markers of N. Gonorrhoeae resistance to β-lactam antibiotics

A complex method for detection of genetic markers of N. gonorrhoeae resistance to penicillin was developed. Mutations in penA and ponA genes were detected by minisequencing reaction with subsequent detection of reaction products by MALDI-TOF mass spectrometry. This approach was tested on 31 clinical strains of N. gonorrhoeae with minimum inhibitory concentration of penicillin from 0.03 to 8 μg/ml and higher. Mutations in penA and ponA genes in moderately resistant strains were shown (minimum inhibitory concentration up to 0.5 μg/ml) and mutations in penA, ponA, and penB genes in resistant strains (minimum inhibitory concentration more than 1.0 μg/ml). β-Lactamase genes were detected in 4 strains with high resistance (minimum inhibitory concentration 4–8 and more μg/ml). Correlation between microbiological resistance and presence of respective mutations in the studied locuses was detected. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 141, No. 5, pp. 549–554, May, 2006     

Management of colorectal cancer: A role for genetics in prevention and treatment?

Colorectal cancer remains one of the most common cancers in the Western world and amongst the top three causes of cancer morbidity and death. Cancer is caused by genetic mutations, but currently there is little use of genetic information in the clinic with the exception of establishing germline mutations for the uncommon predisposing syndromes. Rapid advances in technologies allowing high throughput analysis of germline and somatic mutations raises the possibility that genetics will find a major role in the clinic distinguishing individuals at low to high risk of cancer, allowing early intervention and stratification of cancers based on mutational pathways for therapeutic interventions. In the future, this will lead to treatment regimes tailored to the individuals and their tumor. Here, we summarize the genetics underlying colorectal cancer and the future role of genetics in prevention, diagnosis, classification and treatment.     

Meta-analysis of associations between interleukin-10 polymorphisms and susceptibility to Behcet’s disease

Immunologic Research - The aim of this study was to determine whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to Behcet’s disease (BD). A meta-analysis was...     

A bridge between neuroscience and oncology: prostate cancer genesis. A 'negative' consequence of learning?

Prostate cancer has become the most commonly diagnosed cancer in men over recent years. The initiating mechanism for tumorigenesis within the prostate remains an unknown. The observation, that the cancer incidence in patients with chronic neurological disabilities is significantly lower than in the normal population lead to the hypothesis, that changed processing due to a barrage of aberrant sensory information within a healthy CNS can trigger events within the prostate cell, that cause malignant transformation. There is a broad overlap of cellular mechanism of gene expression, that lead to either long term potentiation, learning and memory storage or deregulated differentiation and malignant transformation.     

Prognostic molecular markers in cancer – quo vadis?

Despite the tremendous number of studies of prognostic molecular markers in cancer, only a few such markers have entered clinical practise. The lack of clinical prognostic markers clearly reflects limitations in or an inappropriate approach to prognostic studies. This situation should be of great concern for the research community, clinicians and patients. In the present review, we evaluate immunohistochemical prognostic marker studies in oral squamous cell carcinomas (OSCC) from 2006 to 2012. We comment upon general issues such as study design, assay methods and statistical methods, applicable to prognostic marker studies irrespective of cancer type. The three most frequently studied markers in OSCC are reviewed. Our analysis revealed that most new molecular markers are reported only once. To draw conclusions of clinical relevance based on the few markers that appeared in more than one study was problematic due to between‐study heterogeneity. Currently, much valuable tissue material, time and money are wasted on irrelevant studies.     

Effect of IL-1β and TNF-α polymorphisms on the prognosis and survival of gastric cancer patients

So far, a number of association studies have focused on the effect of polymorphisms in IL-1β and TNF-α genes on the susceptibility to gastric cancer (GC). Here, we evaluate the possible association between common polymorphisms in the IL-1β and TNF-α genes with various clinicopathological characteristics, including overall survival of GC patients. Restriction fragment length polymorphism analysis was performed for IL-1β-31(T?>?C) and IL-1β-511(C?>?T) and TNF-α-857 (C?>?T) polymorphisms in 130 GC patients. IL-1β-31CC and IL-1β-511TT genotypes held a significantly lower risk of lymphatic invasion (IL-1β-31CC vs. others: adjusted OR?=?0.39, 95% CI?=?0.15-0.96, P?=?0.04, IL-1β-511TT vs. others: adjusted OR?=?0.23, 95% CI?=?0.08-0.67, P?=?0.007). The IL-1β-31CC and IL-1β-511TT genotypes were weakly associated with reduced risk of venous invasion (IL-1β-31CC vs. others: adjusted OR?=?0.35, 95% CI?=?0.12-1.05, P?=?0.06, IL-1β-511TT vs. others: adjusted OR?=?0.32, 95% CI?=?0.08-1.20, P?=?0.09). The IL-1β-511TT genotype was also weakly associated with reduced risk of lymph node metastasis (IL-1β-511TT vs. others: adjusted OR?=?0.42, 95% CI?=?0.17-1.04, P?=?0.06). When the TNF-α-857CT and TNF-α-857-TT genotypes were considered as T carrier, the patients with TNF-α-857T carrier showed significantly better overall survival than patients with CC genotype (P?=?0.011). GC patients who have both IL-1β-31 CC and IL-1β-511 TT genotypes and have at least one of protective genotypes (IL-1β-31 CC, IL-1β-511 TT, TNF-α-857 T carrier) were also associated with better prognostic factors, such as lymphatic and venous invasion better survival. IL-1β-31CC, IL-1β-511TT genotype, and TNF-α-857T carrier may have protective effect against GC progression.     

Expression of cancer stem cell markers in basal and penta-negative breast carcinomas – A study of a series of triple-negative tumors

Purpose

Breast cancer is a heterogeneous disease. Immunohistochemistry has given rise to triple-negative carcinoma (TNC). Concomitantly, biological origins of neoplasia and its heterogeneity has been strongly debated in cancer stem cells (CSC) theme. This study investigates the prevalence of basal (BCC) and penta-negative carcinomas (5NC) in TNC and establishes associations with CSC (CD44CD24).

Materials and methods

94 TNC were tested for CK5/6, HER1, CD44 and CD24, evaluated by a simple immunohistochemistry score and correlated with clinicopathological and survival data.

Results

BCC had higher tumor grades than 5NC (p = 0.004). CD44 negativity (p = 0.007) and CD44⁻CD24⁺ phenotype (p = 0.013) were associated with less vascular invasion amongst TNC. CD44 expression was associated with BCC (p = 0.007). CD44⁻CD24^−/low phenotype was associated with 5NC. None of the variables were associated with clinical outcome.

Conclusion

BCC and 5NC are closely related tumor subtypes. CD44⁻CD24^−/low phenotype was associated with 5NC and CD44⁻CD24⁺ phenotype was associated with vascular invasion. These results require histogenetic confirmation in larger studies.