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Background: We examined the methodological quality of guidelines on colorectal cancer genetic susceptibility syndromes., Methods: PubMed, EMBASE, and Google were searched up to July 2010. Adjourned guidelines in English were included. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used to assess their quality, and the reported evidence base of the guidelines was evaluated., Results: The search yielded 17 eligible guidelines: 11 were developed by independent associations, while 6 had national\state endorsement. Only three guidelines performed satisfactorily, achieving a score >50% in all 6 AGREE domains. Mean standardized scores for the 6 AGREE domains were: 'scope and purpose', 83.9 ± 22.5%; 'stakeholder involvement', 35.6 ± 24.9%; 'rigour of development', 48.6 ± 25.3%; 'clarity and presentation', 71.6 ± 19.3%; 'applicability', 33.8 ± 30.1%; 'editorial independence', 42.2 ± 39.7%. Guidelines with national endorsement performed better in all the domains, with a statistically significant difference in three domains. Fifteen guidelines out of 17 were found to be based on research evidence., Conclusions: There is scope, in many areas, for improving the guidelines analysed, among which are the involvement of various professional figures and patients' representatives, and policies for their application. The AGREE instrument is a useful tool and could also be used profitably by guideline developers to improve the quality of recommendations.

The p73 gene (1p36-33) is involved in cancer development through cell growth inhibition by inducing apoptosis in a p53-like manner. The p73 G4C14-to-A4T14 dinucleotide polymorphism, consisting of two single-nucleotide polymorphisms in the non-coding region of exon 2 that are in complete linkage disequilibrium, has been extensively studied in association with cancer risk. We performed a meta-analysis of published studies that examined the association between this p73 G4C14-to-A4T14 polymorphism and cancer by searching for relevant studies on Medline and Embase up to February 28, 2010. Pooling data from 19 case-control studies that included 6510 cancer cases and 5711 controls, we found that carriers of the p73 G4C14-to-A4T14 homozygous variant genotype (AT/AT) had an increased global risk of cancer [odds ratio (OR) = 1.30, 95% confidence interval (CI), 1.03-1.65]. There was no evidence of an effect modification of p73 AT/AT by age, gender, ethnicity or smoking status in subgroup analyses; however, a 1.35-fold statistically significant increased risk was found among individuals <55 years old. In case-only analysis, the homozygous p73 G4C14-to-A4T14 variant of p73 genotype was associated with the presence of the p53 exon 4 Arg72Pro allele (OR = 1.30, 95% CI, 1.02-1.64), which is suggestive of a biological interaction between the two genes in carcinogenesis. In conclusion, the p73 G4C14-to-A4T14 homozygous variant genotype might be a risk factor for cancer, especially in combination with the p53 exon 4 Arg72Pro polymorphism. Further studies looking at p73 G4C14-to-A4T14 and p53 exon 4 Arg72Pro interaction are required to support our findings.

Background: Massively parallel DNA sequencing of cell-free fetal DNA from maternal blood can detect fetal chromosomal abnormalities. Although existing algorithms focus on the detection of fetal trisomy 21 (T21), these same algorithms have difficulty detecting trisomy 18 (T18)., Methods: Blood samples were collected from 1014 patients at 13 US clinic locations before they underwent an invasive prenatal procedure. All samples were processed to plasma, and the DNA extracted from 119 samples underwent massively parallel DNA sequencing. Fifty-three sequenced samples came from women with an abnormal fetal karyotype. To minimize the intra- and interrun sequencing variation, we developed an optimized algorithm by using normalized chromosome values (NCVs) from the sequencing data on a training set of 71 samples with 26 abnormal karyotypes. The classification process was then evaluated on an independent test set of 48 samples with 27 abnormal karyotypes., Results: Mapped sites for chromosomes of interest in the sequencing data from the training set were normalized individually by calculating the ratio of the number of sites on the specified chromosome to the number of sites observed on an optimized normalizing chromosome (or chromosome set). Threshold values for trisomy or sex chromosome classification were then established for all chromosomes of interest, and a classification schema was defined. Sequencing of the independent test set led to 100% correct classification of T21 (13 of 13) and T18 (8 of 8) samples. Other chromosomal abnormalities were also identified., Conclusion: Massively parallel sequencing is capable of detecting multiple fetal chromosomal abnormalities from maternal plasma when an optimized algorithm is used.