Analyses of the pattern of p53 mutations have been essential for epidemiologic studies linking carcinogen exposure and cancer. We were concerned by the inclusion of dubious reports in the p53 databases that could lead to controversial analysis prejudicial to the scientific community.

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic abnormalities occur in all cancers, so BRCA-related pathways are critical because they serve to safeguard genetic content. Although protecting genetic information is a general function, BRCA-related pathways seem largely specific to preventing breast and ovarian cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific clinical effects.

Many oligodendrogliomas (ODG) have been investigated by comparative genomic hybridization (CGH). To visualize characteristic aberration profiles of non-anaplastic in a comparison with anaplastic ODGs, we performed a meta-analysis of the CGH results of all 89 cases published so far. Therefore, we expanded all given aberrations to the maximum of 850 GTG band resolution. The frequencies of each chromosomal band affected by a genetic imbalance were calculated for WHO grades II and III separately. In non-anaplastic ODGs, -1p and -19q were the most prominent aberrations. In anaplastic ODGs, +7, -4q, -9p, -10, and -15q emerged additionally. We could confirm the existence of three disjunct genetically defined subgroups of ODGs, characterized by -1p/-19q (n=58, 65%, subgroup A), +7/-10 (n=6, 7%, subgroup B) or the absence of either of the two patterns (n=25, 28%, subgroup C). Interestingly, we found a unique aberration pattern in subgroup C (-1p31, -4q, -11p15, -18q, -22q, +17p, +17q) that was different from subgroups A and B, which could indicate a unique molecular carcinogenetic pathway of this ODG subset. Scrutinizing published putative progression markers of ODG, we found that only +7, -10, and -15q significantly correlated with a higher grade of malignancy. Summing up, the expansion of the CGH results to the 850 GTG band resolution enabled a meta-analysis to visualize WHO grade-specific aberration profiles in ODG for the first time.

Accurate risk estimates for individuals with a family history of colorectal cancer are important for surveillance strategies. We systematically reviewed the literature on familial risks of colorectal cancer to determine relative risk estimates for categories of family history and translated these relative risk estimates into absolute risk estimates. A random-effects meta-analysis pooled the effect estimates from individual studies and actuarial life-table methods converted relative into absolute risks. Fifty-nine studies were identified including 47 that estimated the relative risk of developing colorectal cancer given at least one affected first-degree relative. The pooled risk estimate was 2.24 (95% CI 2.06 to 2.43) which rose to 3.97 (95% CI 2.60 to 6.06) with at least two affected relatives. A population lifetime risk of 1.8% for a 50-year old increased to 3.4% (95% CI 2.8 to 4.0) with at least one affected relative or 6.9% (95% CI 4.5 to 10.4) with two or more. Accurate absolute risk estimates show how cancer risks vary over time, particularly by pattern of family history and age of individual at-risk.

We sought to evaluate the estimated risk of GSTM1 null genotype and squamous cell carcinoma of the head and neck (SCCHN).

Surveillance colonoscopy plays an important role in the management of asymptomatic patients known to carry and suspected of carrying hereditary nonpolyposis colorectal cancer gene mutations. Although the shortest interval between surveillance examinations may seem to offer the most benefit to patients, excessive use of this procedure may have unwanted consequences. This study was designed to evaluate the evidence and make recommendations regarding the optimal frequency of surveillance colonoscopy and the age at which to initiate surveillance based on the best available evidence.

Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumour in children and potential cause of blindness from therapeutic eye ablation, second tumours in germ line carrier's survivors, and even death when left untreated. The molecular scanning of RB1 in search of germ line mutations lead to the publication of more than 900 mutations whose knowledge is important for genetic counselling and the characterization of phenotypic-genotypic relationships.

The genetic basis of the sporadic form of medullary thyroid carcinoma, derived from "C" cells, is still poorly understood. Somatic mutations of RET proto-oncogene have been reported at a variable frequency ranging from 23% to 69%. The hypothesis that low penetrance factors, such as polymorphisms, might contribute to the phenotype of this neoplasm has been addressed in a few studies conducting to conflicting results. Herein, we studied 100 individuals (50 patients and 50 controls) aiming to compare the frequencies of G691S, L769L, S836S, and S904S RET polymorphisms observed in patients with respect to controls. Furthermore, meta-analysis of published studies including the present results was conducted. To test the contributory role of the above polymorphisms for the development of "C"-cell hyperplasia, we studied a group of 10 individuals selected for having a positive pentagastrin test despite the absence of a RET germline mutation. An over-representation of the G691S polymorphism, particularly in females, was observed in patients with respect to controls, although not reaching the level of significance. Allelic frequencies of the other three polymorphisms were not different in patients and controls. Results obtained in the admittedly small group of individuals with a positive pentagastrin test are unlikely to support a major influence of any polymorphism in the development of "C"-cell hyperplasia. The meta-analysis provided evidence for a significant association of the S691 allele with MTC (odds ratio 1.54, 95% confidence interval 1.12-2.12, p=0.008) and found no significant associations for the other polymorphisms.

Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to cancer risk. However, epidemiologic findings have been inconsistent. The authors conducted meta-analyses of associations between genes in the base excision repair pathway and cancer risk, focusing on three key genes: 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1/APEX1), and x-ray repair cross-complementing group 1 (XRCC1). They found increased lung cancer risk among subjects carrying the OGG1 Cys/Cys genotype (odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.01, 1.53), using 3,253 cases and 3,371 controls from seven studies; this is consistent with experimental evidence that this isoform exhibits decreased activity. They found a protective effect of the XRCC1 194Trp allele for tobacco-related cancers (OR = 0.86, 95% CI: 0.77, 0.95), using 4,895 cases and 5,977 controls from 16 studies; this is compatible with evidence of lower mutagen sensitivity for this allele. The XRCC1 399Gln/399Gln genotype was associated with increased risk of tobacco-related cancers among light smokers (OR = 1.38, 95% CI: 0.99, 1.94) but decreased risk among heavy smokers (OR = 0.71, 95% CI: 0.51, 0.99), suggesting effect modification by tobacco smoking. There was no association between cancer risk and the APE1/APEX1 Asp148Glu and XRCC1 Arg280His polymorphisms. Recommendations for future studies include pooling of individual data to facilitate evaluation of multigenic effects and detailed analysis of effect modification by environmental exposure.

The aim of this study is to summarize the available molecular epidemiologic studies of lung cancer and metabolic genes, such as NAD(P)H quinone reductase 1 (NQO1) and myeloperoxidase (MPO). NQO1 plays a dual role in the detoxification and activation of procarcinogens whereas MPO has Phase I activity by converting lipophilic carcinogens into hydrophilic forms. Variant genotypes of both NQO1 Pro187 Ser and MPO G-463A polymorphisms may be related to low enzyme activity. The Pro/Ser and Ser/Ser genotypes combined of NQO1 was significantly associated with decreased risk of lung cancer in Japanese [random effects odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.56-0.88] among whom the variant allele is common. The variant genotype of MPO was associated with decreased risk of lung cancer among Caucasians (random effects OR = 0.70, 95% CI = 0.47-1.04). Gene-environment interactions in both polymorphisms may be hampered by inaccurate categorization of tobacco exposure. Evidence on gene-gene interactions is extremely limited. As lung cancer is a multifactorial disease, an improved understanding of such interactions may help identify individuals at risk for developing lung cancer. Such a study should include larger sample size and other polymorphisms in the metabolism of tobacco-derived carcinogens and address interactions with smoking status. The effects of polymorphisms are best represented by their haplotypes. In future studies on lung cancer, the development of haplotype-based approaches will facilitate the evaluation of haplotypic effects, either for selected polymorphisms physically close to each other or for multiple genes within the same drug-metabolism pathway.

To identify chromosomal aberrations that differentiate among the Dukes' stages of colorectal cancer (CRC) as well as those that are responsible for the progression into liver metastases, we performed a meta-analysis of data obtained from 31 comparative genomic hybridization (CGH) studies comprising a total of 859 CRCs. Individual copy number profiles for 373 primary tumors and 102 liver metastases were recorded and several statistical analyses, such as frequency, multivariate logistic regression, and trend tests, were performed. In addition, time of occurrence analysis was applied for the first time to copy number changes identified by CGH, and each genomic imbalance was thereby classified as an early or late event in colorectal tumorigenesis. By combining data from the different statistical tests, we present a novel genetic pathway for CRC progression that distinguishes the Dukes' stages and identifies early and late events in both primary carcinomas and liver metastases. Results from the combined analyses suggest that losses at 17p and 18 and gains of 8q, 13q, and 20 occur early in the establishment of primary CRCs, whereas loss of 4p is associated with the transition from Dukes' A to B-D. Deletion of 8p and gains of 7p and 17q are correlated with the transition from primary tumor to liver metastasis, whereas losses of 14q and gains of 1q, 11, 12p, and 19 are late events. We supplement these findings with a list of potential target genes for the specific alterations from a publicly available microarray expression dataset of CRC.

A systematic meta-analysis of observational studies of melanoma and family history, actinic damage and phenotypic factors was conducted as part of a comprehensive meta-analysis of all major risk factors for melanoma. Following a systematic literature search, relative risks were extracted from 60 studies published before September 2002. Fixed and random effects models were used to obtain pooled estimates for family history (RR = 1.74, 1.41-2.14), skin type (I vs. IV: RR = 2.09, 1.67-2.58), high density of freckles (RR = 2.10, 1.80-2.45), skin colour (Fair vs. Dark: RR = 2.06, 1.68-2.52), eye colour (Blue vs. Dark: RR = 1.47, 1.28-1.69) and hair colour (Red vs. Dark: RR = 3.64, 2.56-5.37), pre-malignant and skin cancer lesions (RR = 4.28, 2.80-6.55) and actinic damage indicators (RR = 2.02, 1.24-3.29). Sub-group analysis and meta-regression were carried out to explore sources of between-study variation and bias. Sensitivity analyses investigated reliability of results and publication bias. Latitude and adjustment for phenotype were two study characteristics that significantly influenced the estimates.

Results from studies investigating the relationship between colorectal cancer survival and chromosome 18q allelic imbalance (AI)/loss of DCC expression (LOE) have been inconsistent. We have reviewed and pooled published studies to estimate the prognostic significance of chromosome 18q status more precisely. Data from 27 studies were eligible. Survival data were pooled using standard meta-analysis techniques. Considerable variation between assessment method, marker choice, and threshold for assigning AI/LOE was observed. Pooling data from a 2189 cases from 17 studies showed significantly worse overall survival in patients with AI/LOE (HR = 2.00, 95%CI: 1.49-2.69), maintained both in the adjuvant setting (HR = 1.69, 95%CI:1.13-2.54), and also by method (HR = 1.67, 95%CI: 1.19-2.36, genotyping microsatellites; HR = 3.00, 95%CI: 1.98-4.56, immunohistochemistry). There was however evidence of heterogeneity and publication bias. Cancers with chromosome 18q loss appear to have a poorer prognosis. Prospective studies using consistent methodology are needed to precisely quantify its effect and role in patients with stage II-III disease.

Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent.

Mendelian randomization, the use of common polymorphisms as surrogates for measuring exposure levels in epidemiologic studies, provides one method of assessing the causal nature of some environmental exposures. This can be illustrated by looking at the association between the ALDH2 polymorphism and esophageal cancer. Alcohol drinking is considered a risk factor for esophageal cancer, and exposure to high levels of acetaldehyde, the principal metabolite of alcohol, may be responsible for the increased cancer risk. The ability to metabolize acetaldehyde is encoded by the ALDH2 gene, which is polymorphic in some populations. The ALDH2*2 allele produces an inactive protein subunit, which is unable to metabolize acetaldehyde. An individual's genotype at this locus may influence their esophageal cancer risk through two mechanisms, first through influencing alcohol intake and second through influencing acetaldehyde levels. We have carried out a meta-analysis of studies looking at the ALDH2 genotype and esophageal cancer and found that risk was reduced among *2*2 homozygotes [odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.16-0.80] and increased among heterozygotes (OR, 3.19; 95% CI, 1.86-5.47) relative to *1*1 homozygotes. This provides strong evidence that alcohol intake increases the risk of esophageal cancer and individuals whose genotype results in markedly lower intake, because they have an adverse reaction to alcohol are thus protected. This meta-analysis also provides evidence that acetaldehyde plays a carcinogenic role in esophageal cancer. The two different processes operating as a result of the ALDH2 genotype have implications for the interpretation of studies using the Mendelian randomization paradigm.

Several potential functional polymorphisms (Arg194Trp, Arg280His, Arg399Gln) in the DNA base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been implicated in cancer risk. Our meta-analysis on total of 11,957 cancer cases and 14,174 control subjects from 38 published case-control studies showed that the odds ratio (OR) for the variant genotypes (Trp/Trp + Arg/Trp) of the Arg194Trp polymorphism, compared with the wild-type homozygote (Arg/Arg), was 0.89 [95% confidence interval (95% CI), 0.81-0.98] for all tumor types without between-study heterogeneity. Similarly, the overall risk for the combined variant genotypes (His/His + Arg/His) of the Arg280His, compared with the wild homozygote (Arg/Arg), was 1.19 (95% CI, 1.00-1.42). However, there was no main effect in either recessive or dominant modeling for the Arg399Gln, and the variant Gln/Gln homozygote was not associated with overall cancer risk (OR, 1.01; 95% CI, 0.90-1.14). The analyses suggest that XRCC1 Arg194Trp, Arg280His polymorphisms may be biomarkers of cancer susceptibility and a single larger study with thousands of subjects and tissue-specific biochemical and biological characterization is warranted to further evaluate potential gene-to-gene and gene-to-environment interactions on XRCC1 polymorphisms and cancer risk.

Studies investigating the association between genetic polymorphisms of glutathione S-transferases (GST) and risk of adult brain tumors have reported conflicting results. The rationale of this meta-analysis was to determine whether GST variants increase the susceptibility of adult brain tumors by pooling data.

Two distinct forms of fms-like tyrosine kinase (FLT3) gene aberrations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, have been recognized in a substantial proportion of patients with acute myeloid leukemia (AML). To investigate their prognostic significance, we performed a meta-analysis of the four published studies that provided survival information according to the FLT3 status: ITD, TKD mutation, and wild type. The summary hazard ratios for disease-free survival (DFS) were 1.88 (95% confidence interval (CI) 1.58-2.23; P<0.001) for FLT3 mutations, 1.86 (95% CI: 1.52-2.29; P<0.001) for ITD, and 1.90 (95% CI: 1.40-2.60; P<0.001) for TKD mutation. The corresponding ratios for overall survival were 1.61 (95% CI: 1.37-1.89; P<0.001), 1.68 (95% CI: 1.39-2.03; P<0.001), and 1.37 (95% CI: 0.94-2.01; P=0.104). Neither white blood cell count at diagnosis nor cytogenetic risk category was a significant source of heterogeneity. These findings indicate that FLT3 mutations have an adverse effect on the outcome for AML, and that the negative impact of TKD mutation seems comparable to that of ITD with regard to DFS. Although it should be borne in mind that this meta-analysis was based on data abstracted from observational studies, these results may justify the risk-adapted therapeutic strategies for AML according to the FLT3 status.

To evaluate the clinical value of HER2 overexpression in breast cancer and its prognostic implication in patients with lymph node negative breast carcinoma.

Mutations in the Ki-ras and TP53 genes are the most frequently observed genetic alterations in colorectal cancer (CRC). Ki-ras mutations are mostly found in codons 12 and 13, and less in codon 61. The majority of the TP53 mutations occur in the core domain which contains the sequence-specific DNA binding activity of the protein, and they results in loss of DNA binding. Few centres have sufficient patients to collect detailed information in the large numbers required to determine the impact of individual ki-ras and TP53 genotypes on outcome. Moreover, it has been reported that specific genetic alterations, and not any mutation, might play a different biological role in cancer progression. For these principal reasons, two collaborative studies have been conducted (the RASCAL and the TP53-CRC Collaborative Studies) with the aim of investigating the prognostic role of any, and specific, Ki-ras and TP53 mutations in CRC progression. The results obtained from the RASCAL studies suggest that Ki-ras mutations might have an effect on the survival rate of CRC patients, and that the specific codon 12 glycine/valine mutation might play a role in the progression of this neoplasia. The results of the TP53-CRC International Collaborative Study demonstrate the importance of primary tumor site when analyzing the prognostic value of TP53 mutations in CRC. In addition, different types of TP53 mutation might play a pivotal role in determining the biological behavior of CRC from different sites and hence the prognosis of patients. This meta-analysis produced evidence for interesting tumor site differences in the predictive value of TP53 mutation for survival benefit from 5FU chemotherapy.