To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996-July 2009). Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04-1.30), MTRR A66G (OR=0.73, 95%CI:0.59-0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65-0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11-1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11-1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32-3.00) NQO1 C609T (OR=1.24, 95%CI:1.02-1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32-2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design.

MammaPrint(®) is a micromatrix based test and the result classifies analyzed tumors as low or high risk for recurrence of breast carcinoma. By analyzing the individual activity of these genes, MammaPrint(®) estimates the response to chemotherapy and/or predicts the outcome of the breast neoplasia. We aimed to assess the clinical and analytical validity of MammaPrint(®) that determines individual risk of relapse of breast cancer.

Mitochondria are sub-cellular organelles that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). As suggested over 70 years ago by Otto Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and in mitochondrial DNA (mtDNA) appear to be common features of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells, and some reports document the prevalence of inherited mitochondrial DNA polymorphisms in cancer patients. Nevertheless, a careful reanalysis of methodological criteria and methodology applied in those reports has shown that numerous papers can't be used as relevant sources of data for systematic review, meta-analysis, or finally for establishment of clinically applicable markers. In this review technical and conceptual errors commonly occurring in the literature are summarized. In the first place we discuss, why many of the published papers cannot be used as a valid and clinically useful sources of evidence in the biomedical and healthcare contexts. The reasons for introduction of noise in data and in consequence - bias for the interpretation of the role of mitochondrial DNA in the complex process of tumorigenesis are listed. In the second part of the text practical aspects of mtDNA research and requirements necessary to fulfill in order to use mtDNA analysis in clinics are shown. Stringent methodological criteria of a case-controlled experiment in molecular medicine are indicated. In the third part we suggest, what lessons can be learned for the future and propose guidelines for mtDNA analysis in oncology. Finally we conclude that, although several conceptual and methodological difficulties hinder the research on mitochondrial patho-physiology in cancer cells, this area of molecular medicine should be considered of high importance for future clinical practice.

The estrogen signal is mediated by the estrogen receptor (ER). The specific role of ER-beta, a second ER, in breast carcinogenesis is not known. A number of association studies have been carried out to investigate the relationship between polymorphic sites in the ESR2 gene and breast cancer risk, however, the results are inconsistent. We searched PubMed, Medline, and Web of Science database (updated to 10 January 2010) and identified 13 relevant case-control studies, and approximately 28 single-nucleotide polymorphisms (SNPs) and one micro-satellite marker were reported in the literature. The median number of study subjects was 776 (range 158-13,550). Three genetic variants [(CA)n, rs2987983, and rs4986938] showed significant overall associations with breast cancer, and rs4986938 was reported twice. Because rs4986938 and rs1256049 were the most extensively studied polymorphisms, we subsequently conducted a meta-analysis to evaluate their relationship with breast cancer risk (9 studies of 10,837 cases and 16,021 controls for rs4986938; 8 studies of 11,652 cases and 15,726 controls for rs1256049). For rs4986938, the women harboring variant allele seemed to be associated with a decreased risk either in the dominant model [pooled OR = 0.944, 95% confidence interval (95% CI) 0.897-0.993, fixed-effects] or in the co-dominant model (AG vs. GG) (OR = 0.944, 95% CI 0.895-0.997, fixed-effects). rs1256049 was not associated with breast cancer risk in any model. Five studies had investigated the effect of haplotypes in the ESR2 gene on breast cancer risk, and four of them had positive outcomes. In summary, the present systematic review suggests that SNP rs4986938 as well as haplotypes in the ESR2 gene might be associated with breast cancer. The need for additional studies examining these issues seems of vital importance.

To systematically review and meta-synthesise primary qualitative research findings regarding family communication following genetic testing of cancer risk, in order to inform development of effective interventions. Systematic searches of CINAHL, Embase, Medline, British Nursing Index and PsycINFO databases were undertaken and relevant studies identified using strict criteria. The selected primary qualitative studies were appraised for quality and relevance by three independent researchers and then synthesized using a "Framework" approach. Fourteen (4.3%) studies met the inclusion criteria. The following factors influenced family communication following genetic testing for late-onset hereditary cancer: the informant's feelings about informing relatives about genetic testing; the perceived relevance of the information to other family members and their anticipated reactions; the "closeness" of relationships within the family; family rules and patterns (e.g., who is best placed to share information with whom); finding the right time and level of disclosure; and the supportive role of heath care professionals. The themes identified in this review could provide practitioners with a useful framework for discussing family communication with those undergoing genetic testing. This framework focuses on helping health care professionals to facilitate family communication. The next step will be the development of an intervention to directly support people in talking to their relatives.

Reports of BRCA genetic mutations and risk of death or recurrence are inconsistent. This study aimed to compare overall and disease-free breast cancer survival rates between BRCA1/2 mutation carriers and non-carriers for short-term and long-term outcomes separately. We searched the PUBMED and EMBASE databases and retrieved 452 articles using keywords that included breast cancer, BRCA mutation, and survival. Seventeen articles were selected for systematic review and among them 11 were included in our meta-analysis. We used the random-effects model to calculate the summary hazard ratio and corresponding 95% confidence interval. BRCA1 mutation carriers had significantly lower short-term and long-term overall survival rates (OSR) relative to non-carriers (HR = 1.92 [95% CI = 1.45-2.53]; 1.33 [1.12-1.58], respectively), while both short-term and long-term OSR of BRCA2 carriers did not differ from non-carriers (HR = 1.30 [95% CI = 0.95-1.76]; 1.12 [95% CI = 0.86-1.45], respectively). For short-term progression-free survival rate (PFSR), BRCA1 mutation carriers had a significantly lower rate than non-carriers (HR = 1.54 [95% CI = 1.12-2.12]), while BRCA2 mutation carriers had a similar PFSR (HR = 1.23 [95% CI = 0.96-1.58]). For long-term PFSRs, we found no significant results. Our results suggest that BRCA1 mutation decreases short-term and long-term OSRs and short-term PFSR, however, BRCA2 mutation does not affect either short-term or long-term survival rate, which is attributed to the different carcinogenic pathways for BRCA1 and BRCA2.

A number of studies has evaluated the association between P53 codon 72 polymorphism and colorectal cancer. However, results were inconsistent. To clarify the role of this polymorphism in colorectal cancer, we conducted a meta-analysis on this topic.

In view of the essential role of transforming growth factorβ1 (TGFB1) on both inhibiting the development of early benign breast tumors as well as promoting tumor invasion, the association of TGFB1 L10P polymorphism and breast cancer risk has been widely reported, but results of previous studies were somewhat contradictory and underpowered. To overcome the limitations of individual study and to understand the real situation, we conducted a systematic review and meta-analysis towards the association between TGFB1 L10P polymorphism and breast cancer. Through retrieving MEDLINE, PubMed, Embase, and Web of Science, a total of 16 studies with 10,392 cases and 11,697 controls were identified. The results showed that significant association was found in the recessive genetic model for Caucasian (OR = 1.152, 95% CI = 1.020-1.301). However, we did not find any associations in additive genetic model (PP vs. LL for total: OR = 1.026, 95% CI = 0.940-1.121), allele contrast (L vs. P for total: OR = 1.004, 95% CI = 0.966-1.044), and dominant genetic model (PP + LP vs. LL for total: OR = 1.001, 95% CI = 0.946-1.061). Conclusively, this meta-analysis strongly suggests that TGFB1 L10P polymorphism may play a low penetrance role in breast cancer susceptibility in Caucasian. Large well-designed epidemiological studies will be necessary to validate the risk identified in the current meta-analysis.

Survivin has gradually become an important target in diagnosis, prognosis prediction and treatment of tumor. There are many studies on urine-based survivin mRNA test using reverse transcription-polymerase chain reaction (RT-PCR) as a noninvasive examination for bladder cancer. However, its clinical value remains controversial. This study was to evaluate the diagnostic value of urine survivin mRNA detection with RT-PCR for bladder cancer by a systematic review of related studies.

Polymorphisms within interleukin-1 (IL1) and tumor necrosis factor alpha (TNFA) gene clusters are associated with an increased risk of gastric cancer. However, their role in gastric precancerous lesions remains poorly understood. Our objective was to perform a meta-analysis of studies addressing the association between IL1B-511, IL1RN variable number of tandem repeat, and TNFA-308 gene polymorphisms and gastric precancerous lesions, including original data from Portugal and Mozambique. Published studies on the association between these cytokine gene polymorphisms and gastric precancerous lesions were identified by systematic review, and estimates of the association were combined using random-effects meta-analysis taking into account new data obtained from Portuguese volunteer shipyard workers (n = 215) and Mozambican dyspeptic patients (n = 96) who underwent endoscopic and pathologic evaluation following the same protocol. Odds ratio (OR) estimates for intestinal metaplasia were 2.83 [95% confidence interval (95% CI), 1.15-6.96] for the IL1RN*22 genotype, 1.86 (95% CI, 1.03-3.36) for IL1B-511 T carriers, and 0.59 (95% CI, 0.12-3.04) for the TNFA-308*AA genotype in the Portuguese sample. All Mozambican subjects with intestinal metaplasia were T carriers for IL1B-511 and none had the 2 allele for IL1RN. In meta-analysis, IL1RN*22 genotype was associated with an increased risk of gastric precancerous lesions (22 versus LL: OR, 2.27; 95% CI, 1.40-3.70; I(2) = 26.4%; 12 studies). No such association was found for the IL1B-511 (TT versus CC: OR, 1.34; 95% CI, 0.87-2.07; I(2) = 65.7%; 13 studies) or TNFA-308 genotypes (AA versus GG: OR, 0.93; 95% CI, 0.35-2.43; I(2) = 0.0%; 7 studies). The IL1RN*22 genotype seems to consistently increase the risk of gastric precancerous lesions, supporting a role for this polymorphism in the early stages of gastric carcinogenesis.

The published data on the predictive value of polymorphism of ERCC1 and XPD in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Relevant studies were identified by searching the Medline, Embase, CNKI and American Society of Clinical Oncology abstract databases. Inclusion criteria were patients with advanced NSCLC, received platinum-based chemotherapy, evaluation of polymorphism of ERCC1 and XPD and overall response rate (ORR). A total of 12 studies were included in this meta-analysis. For studies evaluating ERCC1 polymorphism at codon 118, the ORR for the wild-type C/C genotype versus the heterozygous C/T and T/T genotype was 2.17 (95% confidence interval (CI), 1.43-3.33; P = 0.000). For studies evaluating XPD Asp312Asn and XPD Lys751Gln, the pooled OR was 1.33 (95% CI, 0.92-1.91; P = 0.13) and 1.02 (95% CI, 0.72-1.45; P = 0.915), respectively. The results indicated that platinum-based chemotherapy sensitivity was significantly associated with polymorphism of ERCC1 C118T. However, XPD Asp312Asn and XPD Lys751Gln were not predictive makers for platinum-based chemotherapy in patients with advanced NSCLC.

To summarize existing evidence about whether the presence of mutant or upregulated p53 is a prognostic factor for patients presenting with squamous cell carcinoma arising from the larynx, oropharynx, hypopharynx, or oral cavity.

The fms-like tyrosine kinase 3 (FLT3) gene aberrations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are frequent in acute promyelocytic leukemia (APL). To evaluate their prognostic significance, we performed a systematic review and meta-analysis. Eleven studies covering a total of 1063 subjects were included in this review. Incidence of ITD and TKD mutations was 12-38% and 2-20%, respectively. In 9 of 11 studies, ITD was associated with high WBC count at the time of diagnosis, which is a known prognostic indicator in APL. Patients with ITD had inferior 3-year overall survival compared to patients without ITD (risk ratio 1.42, 95% CI: 1.04-1.95). Similarly, ITD was also associated with adverse 3-year disease-free survival (risk ratio 1.48, 95% CI: 1.02-2.15). There were only two studies that evaluated the association of TKD mutation in APL; both showed a trend towards worse survival in patients with mutated TKD. In conclusion, FLT3 ITD is associated with high WBC at diagnosis in patients with APL. Although the available literature is limited to observational studies, our systematic review suggests that FLT3 mutations, especially ITD, can adversely affect overall survival and disease-free survival in APL.

The National Institutes of Health Office of Medical Applications of Research commissioned a structured literature review on the incidence, treatment, and outcomes of ductal carcinoma in situ (DCIS) as a background article for the State of the Science Conference on Diagnosis and Management of DCIS.

Melanoma commonly clusters in families, and the recent identification of numerous genotypes predicting higher risks of melanoma has led to the widespread perception that this cancer is predominantly a genetic disease. We conducted a systematic review of the literature and meta-analysis to quantify the contribution of familial factors to melanoma, estimated by the population attributable fraction (PAF). Eligible studies were those that permitted quantitative assessment of the association between histologically confirmed melanoma and family history of the disease; we identified 22 such studies using citation databases, followed by manual review of retrieved references. We calculated summary RRs using weighted averages of the log RR, taking into account random effects, and used these to estimate the PAF. Overall, family history was associated with a significant 2-fold increased risk of melanoma (odds ratio, 2.06; 95% confidence interval, 1.72-2.45); however, there was significant heterogeneity (P = 0.01). The pooled estimate for population-based studies (n = 11) was 2.03 (1.70-2.43), and 2.51 (1.55-4.07) for clinic/hospital-based studies (n = 11), both with significant heterogeneity (P = 0.049 and P = 0.013, respectively). Two studies used record linkage to verify family history in relatives; the pooled risk estimate from these two studies was 2.52 (2.11-3.00) with no evidence of heterogeneity (P = 0.258). Estimates of PAF associated with a positive family history ranged from 0.007 for Northern Europe to 0.064 for Australia (0.040 for all regions combined). Our findings suggest that only a small percentage of melanoma cases (always <7%) are attributable to familial risk; the majority of melanomas are presumably attributable to other factors.

The association of CYP19 gene polymorphisms with breast cancer has been widely reported, but results of previous studies were somewhat contradictory and underpowered. In order to overcome the limitations of individual study and to understand the real situation, we conducted a systematic review and meta-analysis including three CYP19 gene polymorphisms [R264C polymorphism, CYP19_630 3-bp del/Ins polymorphism, and CYP19_681 (TTTA)(n) polymorphisms]. A total of 22 studies with 10,592 cases and 11,720 controls were identified, and the results showed that R264C polymorphism was not associated with breast cancer risk in overall (T vs. C: OR = 1.061, 95% CI = 0.929-1.212) or race-based populations (T vs. C for Asian: OR = 1.169, 95% CI = 1.002-1.363; for Caucasian: OR = 0.787, 95% CI = 0.597-1.037); meanwhile, for Asian individuals, 3-bpDel/Ins polymorphism showed a significantly association with breast cancer susceptibility (for allele Del vs. allele Ins: OR = 1.278, 95% CI = 1.066-1.532) while the carriers of allele (TTTA)(12) can significantly decrease breast cancer risk (OR = 0.752, 95% CI = 0.603-0.939). Furthermore, the carriers of allele (TTTA)(10) were significantly associated with breast cancer susceptibility (OR = 1.515, 95% CI = 1.115-2.058). It can be concluded that potentially functional CYP19_630 3-bp del/Ins polymorphism and CYP19_681 (TTTA)(n) polymorphisms may play a low penetrance role in breast cancer susceptibility in an ethnicity-specific manner.

Breast cancer is the most common cancer in women worldwide, but its etiology is still unclear. It is believed that oxidative stress plays an essential role in the development of breast cancer, while SOD2 is one of the primary enzymes that directly convert potential harmful oxidizing species to harmless metabolites. The association of SOD2 Val16Ala polymorphism and breast cancer risk has been widely reported, but results of previous studies were somewhat contradictory and underpowered. To overcome the limitations of individual study and to understand the real situation, we conducted a systematic review and meta-analysis toward the association between SOD2 Val16Ala polymorphism and breast cancer. Through retrieving MEDLINE, PubMed, Embase, and Web of Science, a total of 17 studies with 9,710 cases and 11,041 controls were identified. The results showed that no significant associations were found for the allele contrast (allele Ala vs. allele Val: OR = 1.020, 95% CI = 0.979-1.062), additive genetic model (Ala/Ala vs. Val/Val: OR = 1.091, 95% CI = 0.969-1.229), dominant genetic model (Ala/Ala +Ala/Val vs. Val/Val: OR = 1.045, 95% CI = 0.961-1.136), and recessive genetic model (Ala/Ala vs. Val/Val +Ala/Val: OR = 1.027, 95% CI = 0.956-1.102). In the stratified analysis by ethnicity and menopausal status, significant associations were also not detected in all genetic models. Conclusively, this meta-analysis strongly suggests that SOD2 Val16Ala polymorphism is not associated with breast cancer susceptibility.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder associated with increased cancer risk. Surveillance and patient management are, however, hampered by a wide range in cancer risk estimates. We therefore performed a systematic review to assess cancer risks in PJS patients and used these data to develop a surveillance recommendation.

The aim of this systematic review and meta-analysis was to characterize common EGFR molecular aberrations as potential predictive biomarkers for response to monotherapy with tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC).

Quantitative analysis of circulating cell free DNA is considered as a possible aid for lung cancer screening. We aimed to comprehensively review the evidence for use of circulating cell free DNA to screen for lung cancer.