PubMed Health⌕ Search

Biomedical subjects

Olivia Fletcher

Publications and source records attributed to Olivia Fletcher.

9 recordsLinked to original sources
PubMed2006

Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives.

To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing. Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATM F858L [OR=1.48; 95% confidence interval (CI): 1.06-2.07] and P1054R (OR=1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95% CI: 0.69-0.97). To validate associations, we performed a kin-cohort analysis on the 14 704 first-degree relatives of cases for each SNP associated at the 5% level in the case-control analysis employing the marginal maximum likelihood method to infer genotypes of relatives. Our observations support the hypothesis that inherited predisposition to CRC is in part mediated through polymorphic variation and identify a number of SNPs defining inter-individual susceptibility. We have made data from this analysis publicly available at http://www.icr.ac.uk/research/research_sections/cancer_genetics/cancer_genetics_teams/molecular_and_population_genetics/software_and_databases/index.shtml in order to facilitate the identification of low penetrance CRC susceptibility alleles through pooled analyses.

Aged↗
PubMed2006

Inconsistent association between the STK15 F31I genetic polymorphism and breast cancer risk.

STK15 may be a low-penetrance breast cancer susceptibility gene, and several reports suggest that women who are homozygous for the polymorphic variant F31I have an increased risk of breast cancer. To evaluate this potential breast cancer allele, we genotyped 507 patients with two primary breast cancers and 875 population-based control subjects for the STK15 F31I polymorphism. All statistical tests were two-sided. The Ile/Ile homozygous genotype was not associated with an increased risk in white women of British descent. The odds ratio for developing two primary breast cancers) in Ile/Ile homozygotes was 0.63 (95% confidence interval [CI] = 0.34 to 1.13), which corresponds to an odds ratio of 0.79 (95% CI = 0.58 to 1.06) for a first primary breast cancer. A meta-analysis of this study and other published studies showed statistically significant heterogeneity in the odds ratio estimates (P<.001). This heterogeneity could reflect either population-specific linkage disequilibrium with a functional variant or artifacts such as population stratification or publication bias.

Asian People↗
PubMed2006

The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women.

High levels of circulating insulin-like growth factor-I (IGF-I) and its major binding protein (IGFBP-3) at premenopausal ages have been associated with an increased breast cancer risk. We conducted a cross-sectional study (215 premenopausal women and 241 after natural menopause) nested within the Guernsey prospective studies to examine the relationship between the IGF system and mammographic features of the breast. The mammographically dense area in the breast increased with increasing serum levels of IGF-I (P for linear trend, P(t) = 0.05), IGF-II (P(t) = 0.08), and IGFBP-3 (P(t) = 0.01) only in premenopausal women. IGF-II and IGFBP-3 serum levels were associated with increases in the mammographically lucent area in both premenopausal (P(t) = 0.01 and 0.04, respectively) and postmenopausal women (P(t) < 0.001 for both), but these associations were no longer statistically significant after adjustment for body mass index and waist circumference. Neither the IGF-I/IGFBP-3 nor the IGF-II/IGFBP-3 molar ratio was associated with any of these mammographic features. The number of A alleles at a polymorphic locus in the promoter region of the IGFBP-3 gene was associated with increasing mean IGFBP-3 levels in both premenopausal (P(t) = 0.01) and postmenopausal (P(t) <0.001) women but not with mammographically dense area. These results support the hypothesis that the IGF system may affect the amount of mammographically dense tissue in premenopausal women, possibly by promoting cell proliferation and inhibiting apoptosis in the fibroglandular tissue. The findings also show strong relations between IGF-II and IGFBP-3 levels and the amount of mammographically lucent tissue, reflecting the associations between body adiposity and amount of fat tissue in the breast and between body adiposity and circulating levels of these growth factors.

Adult↗
PubMed2005

Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review.

We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF) and their binding proteins (IGFBP), polymorphisms in their genes, and breast cancer risk. In premenopausal women, five of eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5' to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no convincing evidence of any effect. For an A/C polymorphism 5' to IGFBP-3, all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation. Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely.

Biomarkers, Tumor↗
PubMed2004

Lifetime risks of common cancers among retinoblastoma survivors.

BACKGROUND: Compared with the general population, carriers of germline mutations in RB1 who survive retinoblastoma (i.e., hereditary retinoblastoma survivors) are at increased risk of early-onset second cancers, particularly sarcomas, brain tumors, and melanoma. However, their risks for the epithelial cancers that commonly occur after age 50 years are not known. METHODS: We used hospital records to identify British retinoblastoma survivors born between 1873 and 1950, a period when few British retinoblastoma patients received high-dose radiotherapy. Cancers and deaths were identified by linkage with national registration records. All statistical tests were two-sided. RESULTS: We could trace the cancer histories of 144 survivors of hereditary retinoblastoma. From age 25 to age 84, there were 58 subsequent cancers, for a cumulative cancer incidence of 68.8% (95% confidence interval [CI] = 48.0% to 87.4%) and a cumulative cancer mortality of 56.3% (95% CI = 40.5% to 73.3%). Only eight of the 58 cancers were of bone or soft tissue, in marked contrast to findings from contemporary studies of American patients treated with external beam radiotherapy, among whom most second tumors are sarcomas. Compared with the general population, hereditary retinoblastoma survivors had higher mortality from lung cancer (standardized mortality ratio [SMR] = 7.01, 95% CI = 3.83 to 11.76), bladder cancer (SMR = 26.31, 95% CI = 8.54 to 61.41), and all other epithelial cancers combined (SMR = 3.29, 95% CI = 1.64 to 5.89). The overall standardized mortality ratio for epithelial cancer was inversely proportional to the approximate square of age (exponent of age = -2.1, 95% CI = -3.6 to -0.7), declining from 11.32 (95% CI = 4.15 to 24.64) at age 25-44 to 2.83 (95% CI = 1.04 to 6.16) at age 65-84. CONCLUSIONS: Survivors of hereditary retinoblastoma who are not exposed to high-dose radiotherapy have a high lifetime risk of developing a late-onset epithelial cancer. Most of the excess cancer risks in hereditary retinoblastoma survivors might be preventable by limiting exposures to DNA damaging agents (radiotherapy, tobacco, and UV light).

Adult↗
PubMed2002

Interpreting information: what is said, what is heard--a questionnaire study of health professionals and members of the public.

OBJECTIVE: To investigate how people perceive some of the words and phrases commonly used in prenatal diagnosis counselling. METHODS: A questionnaire containing 25 questions with forced choice answers was administered in the form of a lecture. Respondents were asked to report how worrying they would find different ways of being told about hypothetical anomalies or risks of anomalies in their baby. 581 questionnaires were completed by 372 health professionals and 209 members of the public. The sample was obtained opportunistically. The exact number of non-responders is not known but is estimated to be less than 5%. RESULTS: Respondents reported being particularly worried by the use of genetic jargon and use of the following words: rare, abnormal, syndrome, disorder, anomaly and high risk. They found risk expressed as 1 in X more worrying than when it was expressed as a percentage, and they consistently reacted as if they estimated the chance of an undesired outcome occurring to be greater than that of a desired outcome occurring when both events were equally likely. CONCLUSIONS: The choice of words used to describe a condition or to inform someone about the level of risk of an adverse event occurring may significantly affect how the person perceives that condition or risk.

Adult↗
PubMedDate not supplied

The cervical cancer epidemic that screening has prevented in the UK.

BACKGROUND: Recent reports suggest that the reduction in mortality achieved by the UK national cervical screening programme is too small to justify its financial and psychosocial costs, except perhaps in a few high-risk women. METHODS: We analysed trends in mortality before 1988, when the British national screening programme was launched, to estimate what future trends in cervical cancer mortality would have been without any screening. FINDINGS: Cervical cancer mortality in England and Wales in women younger than 35 years rose three-fold from 1967 to 1987. By 1988, incidence in this age-range was among the highest in the world despite substantial opportunistic screening. Since national screening was started in 1988, this rising trend has been reversed. INTERPRETATION: Cervical screening has prevented an epidemic that would have killed about one in 65 of all British women born since 1950 and culminated in about 6000 deaths per year in this country. However, these estimates are subject to substantial uncertainty, particularly in relation to the effects of oral contraceptives and changes in sexual behaviour. 80% or more of these deaths (up to 5000 deaths per year) are likely to be prevented by screening, which means that about 100000 (one in 80) of the 8 million British women born between 1951 and 1970 will be saved from premature death by the cervical screening programme at a cost per life saved of about pound 36000. The birth cohort trends also provide strong evidence that the death rate throughout life is substantially lower in women who were first screened when they were younger.

Adult↗
PubMedDate not supplied

Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study.

BACKGROUND: The allele CHEK2*1100delC doubles the risk of breast cancer in unselected women, but could confer a greater risk in women with a family history of the disease, particularly of bilateral breast cancer. Our aim was to measure the risk of breast cancer in relatives of women with bilateral breast cancer who were carriers of this allele. METHODS: A population-based series of 469 bilateral breast cancer cases ascertained through English cancer registries were genotyped for CHEK2*1100delC. Standardised incidence ratios (SIRs) and cumulative risks were calculated for breast cancer, prostate cancer, and all other cancers in the first-degree relatives of carriers and non-carriers. FINDINGS: The relatives of bilateral cases who were wild-type for CHEK2 had three times the population risk of female breast cancer (145 cases: SIR 3.48 (95% CI 2.96-4.09), twice the risk of prostate cancer (34 cases: SIR 2.41, 1.67-3.36) and a large excess of male breast cancer (five cases: SIR 15.06, 4.92-35.36). Relatives of those who were carriers of CHEK2*1100delC had a substantially higher risk of breast cancer (eight cases: SIR 12.11, 5.23-23.88) and possibly prostate cancer (two cases: SIR 9.87, 1.20-35.67). INTERPRETATION: These data suggest a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. In women with a family history of bilateral disease, CHEK2*1100delC confers a high lifetime risk and might be useful for predictive testing. Bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast-cancer genes.

Adult↗