To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 × 10 −17 ) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.Lung cancer is frequently cited as a malignancy attributable solely to environmental exposures -primarily cigarette smoke. However, evidence that genetic factors influence lung cancer © 2008 Nature Publishing Group Correspondence should be addressed to C.I.A. (E-mail: camos@mdanderson.org). 6 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS Texas: C.I.A. and M.R.S. conceived of this study. M.R.S. established the Texas lung cancer study. C.I.A. supervised and performed the analyses. G.M. provided oversight in manuscript development and in the conduct of genetic studies. I.P.G., Q.D., Q.Z., W.V.C. and X.G. performed statistical analyses. S.S. developed and implemented statistical procedures for joint analysis. X.W. and J. Direct evidence for a genetic predisposition to lung cancer is provided by the increased risk associated with constitutional TP53 (tumor protein p53) 4 and RB1 (retinoblastoma) 5,6 gene mutations, rare mendelian cancer syndromes such as Bloom's 7 and Werner's syndromes 8 , and strongly familial lung cancer 9 . The genetic basis of inherited susceptibility to lung cancer outside the context of these disorders is at present undefined, but a model in which high-risk alleles account for all of the excess familial risk seems unlikely. Alternatively, part of the inherited genetic risk may be caused by low-penetrance alleles. This hypothesis implies that testing for allelic association should be a powerful strategy for identifying alleles that predispose to lung cancer.We conducted a genome-wide association study (GWAS) of histologically confirmed nonsmall cell lung cancer (NSCLC) to identify common low-penetrance alleles influencing lung cancer risk. To minimize confounding effects from cigarette smoking and increase the power to detect genetic effects, we frequency matched controls to cases according to smoking behavior. We also matched controls to cases by age (within 5 year categories) and sex, and we further matched former smokers by year...

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).

We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 x 10(-10)), 2q37.1 (rs13397985, SP140; P = 5.40 x 10(-10)), 6p25.3 (rs872071, IRF4; P = 1.91 x 10(-20)), 11q24.1 (rs735665; P = 3.78 x 10(-12)), 15q23 (rs7176508; P = 4.54 x 10(-12)) and 19q13.32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.

The importance of information giving has been recognized and promoted in political, ethical and professional arenas and this has ultimately resulted in the publication of a vast amount of literature relating to the subject. This literature review considers the functions of patient information and the factors influencing information seeking for patients who have been diagnosed with cancer. Methods of providing information are discussed and the nurse's role in information giving is examined. A number of core problems are highlighted in relation to information giving. These problems, and possible reasons for them, are subsequently critically analysed. Finally, the literature relating to information needs of patients with cancer is evaluated and five key needs identified.

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 × 10 −10 ), 16q22.1 (rs9929218, CDH1; P = 1.2 × 10 −8 ), 19q13.1 (rs10411210, RHPN2; P = 4.6 × 10 −9 ) and 20p12.3 (rs961253; P = 2.0 × 10 −10 ). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.Whereas inherited susceptibility is responsible for ~35% of all CRC 1 , high-risk germline mutations in APC, the mismatch repair (MMR) genes, MUTYH (MYH), SMAD4, BMPR1A and STK11/LKB1 account for <6% of all cases 2 . Recent GWA studies have validated the hypothesis that part of the heritable risk is caused by common, low-risk variants, identifying CRC susceptibility loci mapping to 8q24 (rs6983267) 3, 4, 8q23.3 (rs16892766, EIF3H)5, 10p14 (rs10795668)5, 11q23 (rs3802842)6, 15q13 (rs4779584)7 and 18q21 (rs4939827, SMAD7) 6,8 .GWA studies are not contingent on prior information concerning candidate genes or pathways, and thereby have the ability to identify important variants in hitherto unstudied genes. However, the effect sizes of individual variants, the need for stringent thresholds for establishing statistical significance, and financial constraints on numbers of variants that can be followed up inevitably constrain study power. We recently published two separate GWA studies for CRC. To augment the power to detect additional CRC risk loci, we have conducted a meta-analysis of data from these studies and followed up the best supported associations in large sample sets. This analysis, in conjunction with a replication study using eight independent case-control series, has enabled us to identify four new loci predisposing to CRC. This brings to ten the number of independent loci conclusively associated with CRC risk, and provides additional insight into the genetic architecture of inherited susceptibility to CRC. RESULTS Meta-analysis of genome-wide association scansThe GWA studies were both conducted by centers in London and Edinburgh, and were both based on designs involving two-phase strategies and using samples from UK populations NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 March 11. Published in final edited form as:Nat Genet. London phase 2 was based on genotyping 2,873 CRC cases and 2,871 controls ascertained through the National Study of Colorectal Cancer Genetics (NSCCG), whereas Edinburgh phase 2 was based on genotyping 2,057 cases and 2,111 controls. For phase 2, the London and Edinburgh samples were genotyped for a common s...

Abstract:Subsurface runoff dominates the hydrology of many steep humid regions, and yet the basic elements of water collection, storage, and discharge are still poorly understood at the watershed scale. Here, we use exceptionally dense rainfall and runoff records from two Northern California watersheds (~100 km 2 ) with distinct wet and dry seasons to ask the simple question: how much water can a watershed store? Stream hydrographs from 17 sub-watersheds through the wet season are used to answer this question where we use a simple water balance analysis to estimate watershed storage changes during a rainy season (dV). Our findings suggest a pronounced storage limit and then 'storage excess' pattern; i.e. the watersheds store significant amounts of rainfall with little corresponding runoff in the beginning of the wet season and then release considerably more water to the streams after they reach and exceed their storage capacities. The amount of rainfall required to fill the storages at our study watersheds is the order of a few hundred millimeters (200-500 mm). For each sub-watershed, we calculated a variety of topographic indices and regressed these against maximum dV. Among various indices, median gradient showed the strongest control on dV where watershed median slope angle was positively related to the maximum volume of storage change. We explain this using a hydrologically active bedrock hypothesis whereby the amount of water a watershed can store is influenced by filling of unrequited storage in bedrock. The amount of water required to activate rapid rainfall-runoff response is larger for steeper watersheds where the more restricted expansion of seepage from bedrock to the soil limits the connectivity between stored water and stream runoff.

We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)).