Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity.

There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.NGB is supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.clon.2015.06.01

Fine-Scale mapping of the 11q13 breast cancer susceptibility locus

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Perallelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, $\small \textit{P}$ = 1.49 x 10$^{-21}$). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity $\small \textit{P}$ $\leq$ 8.41 x 10$^{-5}$). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.Cancer Research UK (Grant IDs: C1287/A10118, C1287/A12014, C490/A10124, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), European Community's Seventh Framework Programme (Grant ID: HEALTH-F2-2009-223175), National Institutes of Health (Grant IDs: CA128978, CA116167, CA176785, CA116201, CA63464, CA54281, CA098758, CA132839, R01CA100374, R01CA64277, R01CA148667, R37CA70867, R01CA092447), National Institute for Health Research. See also Table K via http://dx.doi.org/10.1371/journal.pone.0160316.s003This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.016031

A genome-wide association study to identify genetic markers associated with endometrial cancer grade

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CYP17 5'-UTR MspA1 polymorphism and the risk of premenopausal breast cancer in a German population-based case–control study

INTRODUCTION: Studies on the association between the cytochrome P450c17α gene (CYP17) 5'-untranslated region MspA1 genetic polymorphism and breast cancer risk have yielded inconsistent results. Higher levels of estrogen have been reported among young nulliparous women with the A2 allele. Therefore we assessed the impact of CYP17 genotypes on the risk of premenopausal breast cancer, with emphasis on parity. METHODS: We used data from a population-based case–control study of women aged below 51 years conducted from 1992 to 1995 in Germany. Analyses were restricted to clearly premenopausal women with complete information on CYP17 and encompassed 527 case subjects and 904 controls, 99.5% of whom were of European descent. The MspA1 polymorphism was analyzed using PCR-RFLP (PCR–restriction fragment length polymorphism) assay. RESULTS: The frequencies of the variant allele among the cases and controls were 43% and 41%, respectively. Overall, CYP17 A1/A2 and A2/A2 genotypes compared with the A1/A1 genotype were not associated with breast cancer, with adjusted odds ratios (ORs) of 1.04 and 1.23, respectively. Among nulliparous women, however, breast cancer risk was elevated for the A1/A2 (OR = 1.31; 95% confidence interval (CI) 0.74 to 2.32) and the A2/A2 genotype (OR = 2.12; 95% CI 1.04 to 4.32) compared with the A1/A1 genotype, with a trend towards increasing risk associated with number of A2 alleles (P = 0.04). Otherwise, the CYP17 polymorphism was found neither to be an effect modifier of breast cancer risks nor to be associated with stage of disease. CONCLUSION: Our results do not indicate a major influence of CYP17 MspA1 polymorphism on the risk of premenopausal breast cancer, but suggest that it may have an impact on breast cancer risk among nulliparous women. The finding, however, needs to be confirmed in further studies

Identification of a C/G polymorphism in the promoter region of the BRCA1 gene and its use as a marker for rapid detection of promoter deletions

Reduced expression of BRCA1 has been implicated in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. To determine whether regulatory mutations could account for the reduced expression, we screened the promoter region by sequencing in 20 patients with sporadic disease. No mutations were detected; however, a new polymorphism consisting of a C-to-G base change within the β-promoter was identified, with the frequency of the G allele being 0.34. Close to complete linkage disequilibrium was found between this marker and the Pro871Leu polymorphism, situated in exon 11, which has previously been shown not to be associated with breast or ovarian cancer. This indicates that the C/G polymorphism is also unlikely to play a role in either disease. However, the strength of linkage disequilibrium between these markers permitted their use for rapid screening for genomic deletions within BRCA1. A series of 214 cases with familial breast cancer were analysed using this approach; 88/214 were heterozygous for the promoter polymorphism, thereby excluding a deletion in this region. Among the remaining patients, one hemizygous case reflecting a promoter deletion was successfully identified. Therefore, this study indicates that deletions within the β-promoter region of BRCA1 are an uncommon event in familial breast cancer. Furthermore, it suggests that mutations within the BRCA1 promoter are unlikely to account for the reported decreased expression of BRCA1 in sporadic disease. 1999 Cancer Research Campaig