Review of non-clinical risk models to aid prevention of breast cancer

A disease risk model is a statistical method which assesses the probability that an individual will develop one or more diseases within a stated period of time. Such models take into account the presence or absence of specific epidemiological risk factors associated with the disease and thereby potentially identify individuals at higher risk. Such models are currently used clinically to identify people at higher risk, including identifying women who are at increased risk of developing breast cancer. Many genetic and non-genetic breast cancer risk models have been developed previously. We have evaluated existing non-genetic/non-clinical models for breast cancer that incorporate modifiable risk factors. This review focuses on risk models that can be used by women themselves in the community in the absence of clinical risk factors characterization. The inclusion of modifiable factors in these models means that they can be used to improve primary prevention and health education pertinent for breast cancer. Literature searches were conducted using PubMed, ScienceDirect and the Cochrane Database of Systematic Reviews. Fourteen studies were eligible for review with sample sizes ranging from 654 to 248,407 participants. All models reviewed had acceptable calibration measures, with expected/observed (E/O) ratios ranging from 0.79 to 1.17. However, discrimination measures were variable across studies with concordance statistics (C-statistics) ranging from 0.56 to 0.89. We conclude that breast cancer risk models that include modifiable risk factors have been well calibrated but have less ability to discriminate. The latter may be a consequence of the omission of some significant risk factors in the models or from applying models to studies with limited sample sizes. More importantly, external validation is missing for most of the models. Generalization across models is also problematic as some variables may not be considered applicable to some populations and each model performance is conditioned by particular population characteristics. In conclusion, it is clear that there is still a need to develop a more reliable model for estimating breast cancer risk which has a good calibration, ability to accurately discriminate high risk and with better generalizability across populations.     

CASP8 D302H and meningioma risk: an analysis of five case-control series

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.     

Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma.

Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.     

Antimalarial activities of medicinal plants and herbal formulations used in Thai traditional medicine

Malaria is one of the world's leading killer infectious diseases with high incidence and morbidity. The problem of multidrug-resistant Plasmodium falciparum has been aggravating particularly in Southeast Asia. Therefore, development of new potential antimalarial drugs is urgently required. The present study aimed to investigate antimalarial activities of a total of 27 medicinal plants and 5 herbal formulations used in Thai traditional medicine against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) P. falciparum clones. Antimalarial activity of the ethanolic extracts of all plants/herbal formulations against K1 and 3D7 P. falciparum clones was assessed using SYBR Green I-based assay. All plants were initially screened at the concentration of 50 μg/ml to select the candidate plants that inhibited malaria growth by ≥50 %. Each candidate plant was further assessed for the IC₅₀ value (concentration that inhibits malaria growth by 50 %) to select the potential plants. Selectivity index (SI) of each extract was determined from the IC₅₀ ratio obtained from human renal epithelial cell and K1 or 3D7 P. falciparum clone. The ethanolic extracts from 19 medicinal plants/herbal formulation exhibited promising activity against both K1 and 3D7 clones of P. falciparum with survival of less than 50 % at the concentration of 50 μg/ml. Among these, the extracts from the eight medicinal plants (Plumbago indica Linn., Garcinia mangostana Linn., Dracaena loureiri Gagnep., Dioscorea membranacea Pierre., Artemisia annua Linn., Piper chaba Hunt., Myristica fragrans Houtt., Kaempferia galanga Linn.) and two herbal formulations (Benjakul Formulation 1 and Pra-Sa-Prao-Yhai Formulation) showed potent antimalarial activity with median range IC₅₀ values of less than 10 μg/ml against K1 or 3D7 P. falciparum clone or both. All except G. mangostana Linn. and A. annua Linn. showed high selective antimalarial activity against both clones with SI?>?10. Further studies on antimalarial activities in an animal model including molecular mechanisms of action of the isolated active moieties are required.     

Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma

Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case-control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case-control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14-1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.     

A personalised approach to prostate cancer screening based on genotyping of risk founder alleles

Background:

To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens.

Methods:

A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40–90. Three hundred and twenty-three men with an elevated PSA (⩾4 ng ml⁻¹) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs).

Results:

On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03).

Conclusion:

These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.     

Common variation in Kallikrein genes KLK5, KLK6, KLK12, and KLK13 and risk of prostate cancer and tumor aggressiveness

The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness.Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom.For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04–1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness.Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium.