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1.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis 
Peters, Ulrike | Jiao, Shuo | Schumacher, Fredrick R. | Hutter, Carolyn M. | Aragaki, Aaron K. | Baron, John A. | Berndt, Sonja I. | Bézieau, Stéphane | Brenner, Hermann | Butterbach, Katja | Caan, Bette J. | Campbell, Peter T. | Carlson, Christopher S. | Casey, Graham | Chan, Andrew T. | Chang-Claude, Jenny | Chanock, Stephen J. | Chen, Lin S. | Coetzee, Gerhard A. | Coetzee, Simon G. | Conti, David V. | Curtis, Keith R. | Duggan, David | Edwards, Todd | Fuchs, Charles S. | Gallinger, Steven | Giovannucci, Edward L. | Gogarten, Stephanie M. | Gruber, Stephen B. | Haile, Robert W. | Harrison, Tabitha A. | Hayes, Richard B. | Henderson, Brian E. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Hunter, David J. | Jackson, Rebecca D. | Jee, Sun Ha | Jenkins, Mark A. | Jia, Wei-Hua | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | Lacroix, Andrea Z. | Laurie, Cathy C. | Laurie, Cecelia A. | Le Marchand, Loic | Lemire, Mathieu | Levine, David | Lindor, Noralane M. | Liu, Yan | Ma, Jing | Makar, Karen W. | Matsuo, Keitaro | Newcomb, Polly A. | Potter, John D. | Prentice, Ross L. | Qu, Conghui | Rohan, Thomas | Rosse, Stephanie A. | Schoen, Robert E. | Seminara, Daniela | Shrubsole, Martha | Shu, Xiao-Ou | Slattery, Martha L. | Taverna, Darin | Thibodeau, Stephen N. | Ulrich, Cornelia M. | White, Emily | Xiang, Yongbing | Zanke, Brent W. | Zeng, Yi-Xin | Zhang, Ben | Zheng, Wei | Hsu, Li
Gastroenterology  2012;144(4):799-807.e24.
Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7).
In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID: PMC3636812  PMID: 23266556
Colon Cancer; Genetics; Risk Factors; SNP
2.  RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia 
Nature genetics  2014;46(2):116-125.
The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction; ~30-fold enrichment at promoters and enhancers of genes actively transcribed in B-cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single cell tracking shows that this mechanism is active throughout leukemic evolution with evidence of localized clustering and re-iterated deletions. Integration of point mutation and rearrangement data identifies ATF7IP and MGA as two new tumor suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B-cell differentiation.
PMCID: PMC3960636  PMID: 24413735
4.  IκBKβ and NFκB1, NSAID use and risk of colorectal cancer in the Colon Cancer Family Registry 
Carcinogenesis  2012;34(1):79-85.
The NFκB-signaling pathway regulates cell proliferation and inflammation. Activation of the pathway is implicated in the etiology of colorectal cancer (CRC). NSAIDs may reduce CRC risk partially through a nuclear factor-kappa B (NFκB)-dependent pathway. In this study, we investigated associations between 34 NFκB1 and 8 IκBKβ tagSNPs and CRC risk and examined interactions with non-steroidal anti-inflammatory drug (NSAID) use. Using conditional logistic regression, we investigated these associations among 1584 incident CRC cases and 2516 sibling controls from the Colon Cancer Family Registry. Three IκBKβ SNPs were associated with a statistically significant lower colorectal or colon cancer risk: rs9694958 (A>G intron 5) (colorectal: ORhzv = 0.26(0.07–0.99), Ptrend = 0.048, Padj = 0.25), rs10958713 (A>C intron 19) (colon: ORhzv = 0.62(0.42–0.92), Ptrend = 0.005, Padj = 0.03) and rs5029748 (C>A intron 2) (colon: ORhet = 0.72(0.56–0.91), Ptrend = 0.01, Padj = 0.08). We replicated trends associated with NFκB1 and IκBKβ variants identified in a previous study (rs4648110 (T>A intron 22), rs13117745 (G>A intron 5) and rs3747811 (T>A intron 1)). IκBKβ’s rs6474387 (C>T intron 20) and rs11986055 (A>C intron 2) showed substantially lower colon cancer risk among current NSAID users (Pinteraction = 0.01 and Pinteraction = 0.045, respectively), whereas NFκB1’s rs230490 (G>A 5ʹ (outside UTR)) and rs997476 (C>A 3ʹ (outside UTR)) showed higher CRC risk among current NSAID users (Pinteraction = 0.01 and Pinteraction = 0.03, respectively). These findings suggest that variants in NFκB1 and IκBKβ are associated with CRC risk and NSAIDs may function partially through an NFκB-dependent pathway. The SNPs identified here should be considered for future functional studies and may be useful in designing a pharmacogenetic approach to preventive NSAID use.
PMCID: PMC3534188  PMID: 23002237
5.  A Yearlong Exercise Intervention Decreases CRP among Obese Postmenopausal Women 
Medicine and science in sports and exercise  2009;41(8):10.1249/MSS.0b013e31819c7feb.
To investigate the effect of a yearlong moderate-intensity aerobic exercise intervention on C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) among overweight or obese postmenopausal women.
In a randomized controlled trial, 115 postmenopausal, overweight or obese, sedentary women, aged 50-75 years were randomized to an aerobic exercise intervention of moderate-intensity (60-75% observed maximal heart rate), for ≥45 min/day, 5 days/week (n=53), or to a 1 day/week stretching control (n=62), on an intent-to-treat basis. CRP, SAA, and IL-6 were measured at baseline, 3-months, and 12-months.
From baseline to 12-months, CRP decreased 10% in exercisers and increased 12% in controls (p=0.01); no effects were observed for SAA and IL-6. Among participants at baseline who were obese (BMI≥30kg/m2) or had abdominal obesity (waist circumference (WC)≥88cm), exercise resulted in a more pronounced reduction in CRP (BMI≥30kg/m2: p=0.002; WC≥88cm: p<0.0001), borderline for SAA (BMI≥30kg/m2: p=0.08; WC≥88cm: p=0.04); no intervention effects were observed among women who did not have these characteristics. Overall, weight loss was minimal in the exercise intervention (~1.8kg). Linear trends were observed between CRP and 12-month changes in: aerobic fitness (ptrend = 0.006), exercise adherence (ptrend = 0.004), percentage body fat (ptrend = 0.002), body weight (ptrend = 0.002), waist circumference (ptrend = 0.02), and intra-abdominal fat (ptrend = 0.03).
A moderate-intensity exercise intervention reduced CRP over 12-months among women who were obese at baseline. These findings support the role of exercise in modulating inflammatory processes that are related to increased risk of chronic disease among obese women.
PMCID: PMC3850754  PMID: 19568208
overweight; inflammation; C-reactive protein; physical activity; randomized controlled trial; serum amyloid A
6.  Distinct H3F3A and H3F3B driver variants define chondroblastoma and giant cell tumour of bone 
Nature genetics  2013;45(12):10.1038/ng.2814.
It is recognised that some mutated cancer genes contribute to the development of many cancer types whilst others are cancer-type specific. Amongst genes that affect multiple cancer classes, mutations are usually similar in the different cancer types. Here, however, we observed exquisite tumour-type specificity of different histone 3.3 driver mutations. In 73/77 (95%) cases of chondroblastoma we found K36M mutations predominantly in H3F3B, which is one of two genes encoding histone 3.3. By contrast, 92% (49/53) of giant cell tumours of bone harboured histone 3.3 variants exclusively in H3F3A, which were G34W or, in one case, G34L. The mutations were restricted to the stromal cell population and not detected in osteoclasts or their precursors. In the context of previously reported H3F3A K27M and G34R/V mutations of childhood brain tumours, a remarkable picture of tumour-type specificity of histone 3.3 mutations emerges, indicating distinct functions of histone 3.3 residues, mutations and genes.
PMCID: PMC3839851  PMID: 24162739
7.  A pooled analysis of smoking and colorectal cancer: timing of exposure and interactions with environmental factors 
Considerable evidence suggests that cigarette smoking is associated with a higher risk of colorectal cancer. What is unclear, however, is the impact of quitting smoking on risk attenuation and whether other risk factors for colorectal cancer modify this association.
We performed a pooled analysis of 8 studies, including 6,796 colorectal cancer cases and 7,770 controls to evaluate the association between cigarette smoking history and colorectal cancer risk, and to investigate potential effect modification by other risk factors.
Current smokers (OR=1.26, 95% CI=1.11–1.43) and former smokers (OR=1.18, 95% CI=1.09–1.27), relative to never smokers, showed higher risks of colorectal cancer. Former smokers remained at higher colorectal cancer risk, relative to never smokers, for up to about 25 years after quitting. The impact of time since quitting varied by cancer subsite: the excess risk due to smoking decreased immediately after quitting for proximal colon and rectal cancer, but not until about 20 years post-quitting for distal colon cancer. Further, we observed borderline statistically significant additive interactions between smoking status and BMI (relative excess risk due to interaction [RERI]=0.15, 95% CI:−0.01–0.31, P=0.06) and significant additive interaction between smoking status and fruit consumption (RERI=0.16, 95% CI: 0.01–0.30, P=0.04).
Colorectal cancer risk remained increased for about 25 years after quitting smoking, and the pattern of decline in risk varied by cancer subsite. BMI and fruit intake modified the risk associated with smoking.
These results contribute to a better understanding of the mechanisms through which smoking impacts colorectal cancer etiology.
PMCID: PMC3493822  PMID: 23001243
smoking; colorectal cancer; smoking status; time since quitting smoking; multiplicative and additive interaction; body mass index; vegetable and fruit intake
8.  A Four-Year Field Program Investigating Long-Term Effects of Repeated Exposure of Honey Bee Colonies to Flowering Crops Treated with Thiamethoxam 
PLoS ONE  2013;8(10):e77193.
Neonicotinoid residues in nectar and pollen from crop plants have been implicated as one of the potential factors causing the declines of honey bee populations. Median residues of thiamethoxam in pollen collected from honey bees after foraging on flowering seed treated maize were found to be between 1 and 7 µg/kg, median residues of the metabolite CGA322704 (clothianidin) in the pollen were between 1 and 4 µg/kg. In oilseed rape, median residues of thiamethoxam found in pollen collected from bees were between <1 and 3.5 µg/kg and in nectar from foraging bees were between 0.65 and 2.4 µg/kg. Median residues of CGA322704 in pollen and nectar in the oilseed rape trials were all below the limit of quantification (1 µg/kg). Residues in the hive were even lower in both the maize and oilseed rape trials, being at or below the level of detection of 1 µg/kg for bee bread in the hive and at or below the level of detection of 0.5 µg/kg for hive nectar, honey and royal jelly samples. The long-term risk to honey bee colonies in the field was also investigated, including the sensitive overwintering stage, from four years consecutive single treatment crop exposures to flowering maize and oilseed rape grown from thiamethoxam treated seeds at rates recommended for insect control. Throughout the study, mortality, foraging behavior, colony strength, colony weight, brood development and food storage levels were similar between treatment and control colonies. Detailed examination of brood development throughout the year demonstrated that colonies exposed to the treated crop were able to successfully overwinter and had a similar health status to the control colonies in the following spring. We conclude that these data demonstrate there is a low risk to honey bees from systemic residues in nectar and pollen following the use of thiamethoxam as a seed treatment on oilseed rape and maize.
PMCID: PMC3806756  PMID: 24194871
9.  The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts 
Leukemia  2012;27(4):889-896.
Refractory anemia with ring sideroblasts (RARS) is characterized by mitochondrial ferritin (FTMT) accumulation and markedly suppressed expression of the iron transporter ABCB7. To test the hypothesis that ABCB7 is a key mediator of ineffective erythropoiesis of RARS, we modulated its expression in hematopoietic cells. ABCB7 up and down-regulation did not influence growth and survival of K562 cells. In normal bone marrow, ABCB7 down-regulation reduced erythroid differentiation, growth, and colony formation, and resulted in a gene expression pattern similar to that observed in intermediate RARS erythroblasts, and in the accumulation of FTMT. Importantly, forced ABCB7 expression restored erythroid colony growth and decreased FTMT expression level in RARS CD34+ marrow cells. Mutations in the SF3B1 gene, a core component of the RNA splicing machinery, were recently identified in a high proportion of patients with RARS and eleven of the thirteen RARS patients in this study carried this mutation. Interestingly, ABCB7 exon usage differed between NBM and RARS, as well as within the RARS cohort. In addition, SF3B1 silencing resulted in down-regulation of ABCB7 in K562 cells undergoing erythroid differentiation. Our findings support that ABCB7 is implicated in the phenotype of acquired RARS and suggest a relation between SF3B1 mutations and ABCB7 down-regulation.
PMCID: PMC3794445  PMID: 23070040
Acquired sideroblastic anemia; RARS; ABCB7; SF3B1; iron sulfur cluster biogenesis; mitochondrial ferritin (FTMT)
10.  Obesity-related markers and breast cancer in CPS-II Nutrition Cohort 
Low circulating levels of adiponectin and high levels of insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP), and C-peptide have been shown to be related to postmenopausal breast cancer risk, and to partially mediate the obesity-postmenopausal breast cancer association; however, data from prospective studies, especially those limited to non-users of postmenopausal hormones, are sparse. To further evaluate these associations, we measured these markers in a case-control study nested in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort. Plasma samples from 302 postmenopausal breast cancer cases and matched controls were analyzed. None of the women were taking postmenopausal hormones at blood draw. Multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Low levels of total adiponectin and high levels of total IGF-1 and CRP were associated with increased breast cancer risk, but associations were not statistically significant. The association with C-peptide was statistically significant (T3 vs. T1: OR=1.63, 95% CI 1.08-2.45; p-value for linear trend=0.001), but was slightly attenuated after further adjustment for BMI (T3 vs. T1: OR=1.51, 95% CI 0.99-2.31; p-value for linear trend=0.004). The association between BMI and breast cancer risk was attenuated toward the null after controlling for C-peptide (from OR=1.43 to OR=1.25 for BMI ≥30 kg/m2 compared to <25 kg/m>2). The elevated risk of postmenopausal breast cancer associated with higher circulating levels of C-peptide is consistent with a role of hyperinsulinemia in breast carcinogenesis, and might account for some of the higher risk associated with obesity.
PMCID: PMC3773567  PMID: 24046808
Breast cancer; obesity; C-peptide; risk
11.  Diabetes and Cause-Specific Mortality in a Prospective Cohort of One Million U.S. Adults 
Diabetes Care  2012;35(9):1835-1844.
Diabetes is a major predictor of death from heart disease and stroke; its impact on nonvascular mortality, including specific cancers, is less understood. We examined the association of diabetes with cause-specific mortality, including deaths from specific cancers.
A prospective cohort of 1,053,831 U.S. adults, without cancer at baseline, enrolled in the Cancer Prevention Study-II in 1982 and was followed for mortality until December 2008. At baseline, participants completed a self-administered questionnaire that included information on diabetes, smoking, physical activity, height, and weight. Multivariable-adjusted relative risks (RRs) (95% CI) were estimated using Cox proportional hazards regression.
During 26 years of follow-up, 243,051 men and 222,109 women died. In multivariable models that controlled for age, BMI, and other variables, diabetes was associated with higher risk of all-cause mortality (women RR 1.90 [95% CI 1.87–1.93]; men 1.73 [1.70–1.75]). Among women, diabetes was associated with higher risk of death from cancers of the liver (1.40 [1.05–1.86]), pancreas (1.31 [1.14–1.51]), endometrium (1.33 [1.08–1.65]), colon (1.18 [1.04–1.33]), and breast (1.16 [1.03–1.29]). Among men, diabetes was associated with risk of death from cancers of the breast (4.20 [2.20–8.04]), liver (2.26 [1.89–2.70]), oral cavity and pharynx (1.44 [1.07–1.94]), pancreas (1.40 [1.23–1.59]), bladder (1.22 [1.01–1.47]), colon (1.15 [1.03–1.29]), and (inversely) prostate (0.88 [0.79–0.97]). Diabetes was also associated with higher risks of death involving the circulatory system, respiratory system, digestive system, genitourinary system, and external causes/accidental deaths.
Diabetes is associated with higher risk of death for many diseases, including several specific forms of cancer.
PMCID: PMC3425000  PMID: 22699290
14.  Next generation sequencing in breast cancer: first take home messages 
Current opinion in oncology  2012;24(6):597-604.
Purpose of the review
We are currently on the threshold of a revolution in breast cancer research thanks to the emergence of novel technologies based on next generation sequencing (NGS). In this review, we will describe the different sequencing technologies and platforms, and summarize the main findings from the latest sequencing papers in breast cancer.
Recent findings
First, the sequencing of a few hundreds of breast tumors has revealed new cancer genes. Although these were not frequently mutated, mutated genes from different patients could be grouped into the deregulation of similar pathways. Second, NGS allowed further exploration of intratumor heterogeneity and revealed that although subclonal mutations were present in all tumors, there was always a dominant clone which comprised at least 50% of the tumor cells. Finally, tumor-specific DNA rearrangements could be detected in the patient’s plasma, suggesting that NGS could be used to personalize the monitoring of the disease.
The application of NGS to breast cancer has been associated with tremendous advances and promises for increasing the understanding of the disease. However, there still remain many unanswered questions, such as for example the role of structural changes of tumor genomes in cancer progression and treatment response/resistance.
PMCID: PMC3713550  PMID: 23014189
breast cancer; next generation sequencing; cancer genes; driver/passenger mutations; tumor heterogeneity
15.  Psychiatric symptoms as a clinical presentation of Cushing’s syndrome 
Cushing’s syndrome can present with a spectrum of symptoms; however, it is less recognised that psychiatric symptoms can form part of the clinical presenting features. In the investigations for an organic cause for a psychiatric illness, Cushing’s syndrome needs to be considered, especially if there are other features such as hirsutism or hypertension. In this article, the two cases reported demonstrate that a prompt diagnosis is not only important for psychiatric management but also crucial for timely institution of the necessary treatment of life-threatening causes of hypercortisolaemia such as metastatic adrenal carcinoma.
PMCID: PMC3718650  PMID: 23866099
Hypercortisolaemia; Hypercortisolism; Cushing’s syndrome; Psychosis; Depression; Catatonia
16.  Emerging clinical imaging techniques for cerebral cavernous malformations: a systematic review 
Neurosurgical focus  2010;29(3):E6.
Cerebral cavernous malformations (CCM) are divided into sporadic and familial forms. For clinical imaging, T2-weighted gradient-echo sequences have been shown to be more sensitive than conventional sequences. Recently more advanced imaging techniques such as high-field and susceptibility-weighted magnetic resonance imaging has been employed for the evaluation of CCMs. Furthermore, diffusion tensor imaging and functional magnetic resonance imaging have been applied to the preoperative and intraoperative management of these lesions. In this paper, the authors attempt to provide a concise review of the emerging imaging methods utilized in the clinical diagnosis and treatment of CCMs.
PMCID: PMC3708641  PMID: 20809764
magnetic resonance imaging; cavernoma; cavernous malformations; susceptibility-weighted imaging; gradient echo; functional magnetic resonance imaging
17.  Association Between Colorectal Cancer Susceptibility Loci and Survival Time After Diagnosis With Colorectal Cancer 
Gastroenterology  2012;143(1):51-4.e4.
Genome-wide association studies have identified 16 germline single-nucleotide polymorphisms (SNPs) that are associated with colorectal cancer (CRC) incidence. We examined the relationship between these SNPs and survival of 2611 individuals with CRC, enrolled in 5 cohort studies. We used Cox regression analysis to associate SNPs with overall and CRC-specific survival times. The minor allele in rs4939827 (SMAD7) was associated with reduced overall survival (hazard ratio, 1.16; 95% confidence interval, 1.06–1.27; P = .002) and disease-specific survival (hazard ratio, 1.17; 95% confidence interval, 1.05–1.30; P = .005). Other SNPs were not associated significantly with survival. Common germline variations might be prognostic factors for patients with CRC. A variant in SMAD7 could affect progression of CRC.
PMCID: PMC3579620  PMID: 22580541
Colon Cancer; Genetic; GWAS; Prognosis
18.  Survival after inflammatory bowel disease-associated colorectal cancer in the Colon Cancer Family Registry 
AIM: To investigate the survival of individuals with colorectal cancer (CRC) with inflammatory bowel disease (IBD-associated CRC) compared to that of individuals without IBD diagnosed with CRC.
METHODS: Epidemiologic, clinical, and follow-up data were obtained from the Colon Cancer Family Registry (Colon CFR). IBD-associated cases were identified from self-report of physician diagnosis. For a subset of participants, medical records were examined to confirm self-report of IBD. Cox proportional hazards regression was applied to estimate adjusted hazard ratios (aHR) and 95%CI of mortality, comparing IBD-associated to non-IBD-associated CRC, adjusted for age at CRC diagnosis, sex, Colon CFR phase, and number of prior endoscopies. Following imputation to complete CRC stage information, adjustment for CRC stage was examined.
RESULTS: A total of 7202 CRC cases, including 250 cases of IBD-associated CRC, were analyzed. Over a twelve year follow-up period following CRC diagnosis, 2013 and 74 deaths occurred among non-IBD associated CRC and IBD-associated CRC patients, respectively. The difference in survival between IBD-associated and non-IBD CRC cases was not statistically significant (aHR = 1.08; 95%CI: 0.85-1.36). However, the assumption of proportional hazards necessary for valid inference from Cox regression was not met over the entire follow-up period, and we therefore limited analyses to within five years after CRC diagnosis when the assumption of proportional hazards was met. Over this period, there was evidence of worse prognosis for IBD-associated CRC (aHR = 1.36; 95%CI: 1.05-1.76). Results were similar when adjusted for CRC stage, or restricted to IBD confirmed in medical records.
CONCLUSION: These results support the hypothesis that IBD-associated CRC has a worse prognosis than non-IBD-associated CRC.
PMCID: PMC3671075  PMID: 23745025
Colorectal cancer; Inflammatory bowel disease; Outcomes research; Cancer survival; Inflammation
19.  JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone 
Blood  2012;120(13):2704-2707.
Subclones homozygous for JAK2V617F are more common in polycythemia vera (PV) than essential thrombocythemia (ET), but their prevalence and significance remain unclear. The JAK2 mutation status of 6495 BFU-E, grown in low erythropoietin conditions, was determined in 77 patients with PV or ET. Homozygous-mutant colonies were common in patients with JAK2V617F-positive PV and were surprisingly prevalent in JAK2V617F-positive ET and JAK2 exon 12-mutated PV. Using microsatellite PCR to map loss-of-heterozygosity breakpoints within individual colonies, we demonstrate that recurrent acquisition of JAK2V617F homozygosity occurs frequently in both PV and ET. PV was distinguished from ET by expansion of a dominant homozygous subclone, the selective advantage of which is likely to reflect additional genetic or epigenetic lesions. Our results suggest a model in which development of a dominant JAK2V617F-homzygous subclone drives erythrocytosis in many PV patients, with alternative mechanisms operating in those with small or undetectable homozygous-mutant clones.
PMCID: PMC3672970  PMID: 22898600
20.  Evolution of the cancer genome 
Nature reviews. Genetics  2012;13(11):795-806.
The advent of massively parallel sequencing technologies has allowed the characterization of cancer genomes at an unprecedented resolution. Investigation of the mutational landscape of tumours is providing new insights into cancer genome evolution, laying bare the interplay of somatic mutation, adaptation of clones to their environment and natural selection. These studies have demonstrated the extent of the heterogeneity of cancer genomes, have allowed inferences to be made about the forces that act on nascent cancer clones as they evolve and have shown insight into the mutational processes that generate genetic variation. Here we review our emerging understanding of the dynamic evolution of the cancer genome and of the implications for basic cancer biology and the development of antitumour therapy.
PMCID: PMC3666082  PMID: 23044827
21.  EMu: probabilistic inference of mutational processes and their localization in the cancer genome 
Genome Biology  2013;14(4):R39.
The spectrum of mutations discovered in cancer genomes can be explained by the activity of a few elementary mutational processes. We present a novel probabilistic method, EMu, to infer the mutational signatures of these processes from a collection of sequenced tumors. EMu naturally incorporates the tumor-specific opportunity for different mutation types according to sequence composition. Applying EMu to breast cancer data, we derive detailed maps of the activity of each process, both genome-wide and within specific local regions of the genome. Our work provides new opportunities to study the mutational processes underlying cancer development. EMu is available at
PMCID: PMC3663107  PMID: 23628380
cancer genomes; expectation-maximization; chromatin state; breast cancer; mutation clustering
22.  Single-cell paired-end genome sequencing reveals structural variation per cell cycle 
Nucleic Acids Research  2013;41(12):6119-6138.
The nature and pace of genome mutation is largely unknown. Because standard methods sequence DNA from populations of cells, the genetic composition of individual cells is lost, de novo mutations in cells are concealed within the bulk signal and per cell cycle mutation rates and mechanisms remain elusive. Although single-cell genome analyses could resolve these problems, such analyses are error-prone because of whole-genome amplification (WGA) artefacts and are limited in the types of DNA mutation that can be discerned. We developed methods for paired-end sequence analysis of single-cell WGA products that enable (i) detecting multiple classes of DNA mutation, (ii) distinguishing DNA copy number changes from allelic WGA-amplification artefacts by the discovery of matching aberrantly mapping read pairs among the surfeit of paired-end WGA and mapping artefacts and (iii) delineating the break points and architecture of structural variants. By applying the methods, we capture DNA copy number changes acquired over one cell cycle in breast cancer cells and in blastomeres derived from a human zygote after in vitro fertilization. Furthermore, we were able to discover and fine-map a heritable inter-chromosomal rearrangement t(1;16)(p36;p12) by sequencing a single blastomere. The methods will expedite applications in basic genome research and provide a stepping stone to novel approaches for clinical genetic diagnosis.
PMCID: PMC3695511  PMID: 23630320
23.  DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis 
eLife  2013;2:e00534.
Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis.
eLife digest
The genomes of cancer cells contain mutations that are not present in normal cells. Some of these prevent cells from repairing their DNA, while others give rise to tumours by causing cells to multiply uncontrollably. Moreover, some of the mutations in breast cancer cells occur in clusters—a phenomenon known as kataegis (from the Greek for ‘thunderstorm’).
Kataegic mutations occur almost exclusively at a cytosine preceded by a thymine. This suggests that a family of proteins called AID/APOBEC enzymes—which remove amine groups from cytosines—may be involved in generating these mutations. In this study, Taylor et al. confirm this possibility by showing that expressing individual members of the AID/APOBEC family of enzymes in yeast cells increases the mutation frequency and induces kataegis.
The kataegis triggered by the AID/APOBEC enzymes could be localised through the introduction of double-stranded breaks into the DNA: Taylor et al. suggest that this might happen because repairing the breaks exposes single-stranded DNA, which the AID/APOBEC enzymes then act upon. By comparing the mutations induced in the yeast cells with those observed in breast cancer cells, Taylor et al. identified APOBEC3B as the enzyme most likely to be responsible for kataegis in breast cancer (with APOBEC3A also a strong candidate in some cancers). Moreover, they showed that APOBEC3B was highly expressed in breast cancer cell lines, and that APOBEC3B and APOBEC3A can also cause DNA damage in human cells.
Taken together, the findings provide key insights into the mechanism by which kataegis arises, and identify two proteins likely to contribute to the mutations seen in breast cancer. Further work is now required to determine whether these enzymes also give rise to mutations in other forms of cancer.
PMCID: PMC3628087  PMID: 23599896
Hypermutation; DNA deamination; AID/APOBECs; Kataegis; Cancer; Cytidine deamination; Human; S. cerevisiae
24.  Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions 
The Journal of Clinical Investigation  2013;123(5):2169-2182.
Large regions of recurrent genomic loss are common in cancers; however, with a few well-characterized exceptions, how they contribute to tumor pathogenesis remains largely obscure. Here we identified primate-restricted imprinting of a gene cluster on chromosome 20 in the region commonly deleted in chronic myeloid malignancies. We showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis, 2 lineages commonly affected in chronic myeloid malignancies, with distinct consequences in each lineage. We demonstrated that L3MBTL1 and SGK2 collaborated in the transcriptional regulation of MYC by influencing different aspects of chromatin structure. L3MBTL1 is known to regulate nucleosomal compaction, and we here showed that SGK2 inactivated BRG1, a key ATP-dependent helicase within the SWI/SNF complex that regulates nucleosomal positioning. These results demonstrate a link between an imprinted gene cluster and malignancy, reveal a new pathogenetic mechanism associated with acquired regions of genomic loss, and underline the complex molecular and cellular consequences of “simple” cancer-associated chromosome deletions.
PMCID: PMC3635733  PMID: 23543057
25.  Recurrent SETBP1 mutations in atypical chronic myeloid leukemia 
Nature genetics  2012;45(1):18-24.
Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.
PMCID: PMC3588142  PMID: 23222956

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