Center for Molecular Epidemiology


Center for Molecular Epidemiology

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Chan S.-L.,National University of Singapore | Tan L.L.,Health Products Regulation Group | Toh D.S.-L.,Health Products Regulation Group | Chia K.-S.,National University of Singapore | And 6 more authors.
Pharmacogenetics and Genomics | Year: 2013

The Singapore Pharmacogenomics Portal is the first genomics web platform that links public resources from PharmGKB and DrugBank with population genetics data from the International HapMap Project and the Singapore Genome Variation Project. The web portal provides the opportunity to survey genetic differences across populations for all autosomal genes in the genome, and serves as an integrated platform for linking these data with drugs and genetic variants that affect drug responses, adverse reactions, and dosage requirements. We envisage that the information provided by the portal will be useful to drug regulators and clinical researchers when evaluating the transferability of results from clinical trials conducted in one population to other populations for which no direct clinical testing has been conducted. The utility of this resource may extend to other countries in the region that also have significant populations of Chinese, Malay, or Indian ancestry. © Lippincott Williams and Wilkins.

News Article | November 25, 2016

Nov. 25, 2016, Lebanon, N.H. - Using state-of-the-art molecular biology and statistical approaches, researchers at Dartmouth's Norris Cotton Cancer Center (NCCC) have identified the functional role of two distinct DNA modifications in glioblastoma (GBM) tissues. The signature of one of these pattern disruptions in particular, 5hmC, had a particularly strong association with patient survival. Glioblastoma (GBM) is a rare but deadly type of cancer that originates in the brain. Roughly 12,000 new cases are confirmed in the U.S. each year and its highly infiltrative nature renders it particularly difficult to treat. One of the distorted molecular features of GBM is faulty epigenetic regulation. The epigenome involves modifications to DNA that dictate which genes are turned off and on within a particular cell-type. Defects here are known to contribute to cancer and current methods to predict brain tumor patient prognosis are based on epigenetic tumor subtypes. However, the epigenome is complex and there are recently discovered epigenetic marks that remain understudied in GBM. Led by Cancer Center Member, Brock Christensen, PhD, Associate Professor of Epidemiology at Dartmouth's Geisel School of Medicine, researchers broke new territory by analyzing the profile of multiple DNA modifications, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5-hmC), in a set of 30 glioblastomas in collaboration with clinicians at NCCC. "An intense interest has emerged in detailing the functional role of distinct DNA modifications in both healthy and disease tissues," said Christensen. "Here, we uncovered that specific DNA 5mC and 5hmC patterns are disrupted in GBM and uniquely characterize the molecular switches of the genome known as 'enhancers.' Importantly, we discovered that 5hmC signatures had a particularly strong association with patient survival." Their paper detailing these patterns, "5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients," has been published in Nature Communications. Previous technical limitations prohibited scientists from simultaneously studying high-resolution 5mC and 5hmC levels in a cancer genome. The Dartmouth study utilizes state-of-the-art molecular biology and statistical approaches, including the Dartmouth Discovery Computing Cluster and Nano String nCounter technology, to identify the levels of the distinct DNA modifications across the critical regions of the genome. "Together, our work reveals more about the powerful influence of the epigenome in cancer and highlights the distinct functional role of 5hmC," explains Christensen. This was the first investigation to describe 5hmC distribution in the glioblastoma genome and its relationship with patient survival. Looking ahead, these findings suggest that future mapping of the epigenome in a larger cohort of brain tumors may improve prognosis and help inform treatments. This work was supported by the National Institutes of Health (NIH) Grants R01 DE022772 to BCC and R01 MH094609 to EAH. The research reported in this publication was also supported the Center for Molecular Epidemiology COBRE program with grant funds from the National Institute of General Medical Sciences (NIGMS) of the NIH under Award P20 GM104416. Norris Cotton Cancer Center combines advanced cancer research at Dartmouth's Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua and Keene, NH, and St. Johnsbury, VT, and at partner hospitals throughout New Hampshire and Vermont. It is one of 45 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at

Chuang S.-C.,International Agency for Research on Cancer IARC | Chuang S.-C.,Imperial College London | Scelo G.,International Agency for Research on Cancer IARC | Lee Y.-C.A.,International Agency for Research on Cancer IARC | And 27 more authors.
British Journal of Cancer | Year: 2010

Background:Patterns of second primary cancers (SPCs) following first primary lung cancers (FPLCs) may provide aetiological insights into FPLC.Methods:Cases of FPLCs in 13 cancer registries in Europe, Australia, Canada, and Singapore were followed up from the date of FPLC diagnosis to the date of SPC diagnosis, date of death, or end of follow-up. Standardised incidence ratios (SIRs) were calculated to estimate the magnitude of SPC development following squamous cell carcinoma (SCC), small cell lung carcinoma (SCLC), and adenocarcinoma (ADC).Results:Among SCC patients, male SIR1.58 (95% confidence interval (CI)1.50-1.66) and female SIR2.31 (1.94-2.72) for smoking-related SPC. Among SCLC patients, the respective ratios were 1.39 (1.20-1.60) and 2.28 (1.73-2.95), and among ADC patients, they were 1.73 (1.57-1.90) and 2.24 (1.91-2.61). We also observed associations between first primary lung ADC and second primary breast cancer in women (SIR1.25, 95% CI1.05-1.48) and prostate cancer (1.56, 1.39-1.79) in men.Conclusion:The FPLC patients carried excess risks of smoking-related SPCs. An association between first primary lung ADC and second primary breast and ovarian cancer in women at younger age and prostate cancers in men may reflect an aetiological role of hormones in lung ADC. © 2010 Cancer Research UK All rights reserved.

Madan J.C.,Childrens Hospital at Dartmouth | Madan J.C.,Childrens Environmental Health and Disease Prevention Research Center at Dartmouth | Hoen A.G.,Childrens Environmental Health and Disease Prevention Research Center at Dartmouth | Hoen A.G.,1 Medical Center Dr | And 14 more authors.
JAMA Pediatrics | Year: 2016

IMPORTANCE: The intestinal microbiome plays a critical role in infant development, and delivery mode and feeding method (breast milk vs formula) are determinants of its composition. However, the importance of delivery mode beyond the first days of life is unknown, and studies of associations between infant feeding and microbiome composition have been generally limited to comparisons between exclusively breastfed and formula-fed infants, with little consideration given to combination feeding of both breast milk and formula. OBJECTIVE: To examine the associations of delivery mode and feeding method with infant intestinal microbiome composition at approximately 6 weeks of life. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study of 102 infants followed up as part of a US pregnancy cohort study. EXPOSURES: Delivery mode was abstracted from delivery medical records, and feeding method prior to the time of stool collection was ascertained through detailed questionnaires. MAIN OUTCOMES AND MEASURES: Stool microbiome composition was characterized using next-generation sequencing of the 16S rRNA gene. RESULTS: There were 102 infants (mean gestational age, 39.7 weeks; range, 37.1-41.9 weeks) included in this study, of whom 70 were delivered vaginally and 32 by cesarean delivery. In the first 6 weeks of life, 70 were exclusively breastfed, 26 received combination feeding, and 6 were exclusively formula fed. We identified independent associations between microbial community composition and both delivery mode (P < .001; Q < .001) and feeding method (P = .01; Q < .001). Differences in microbial community composition between vaginally delivered infants and infants delivered by cesarean birth were equivalent to or significantly larger than those between feeding groups (P = .003). Bacterial communities associated with combination feeding were more similar to those associated with exclusive formula feeding than exclusive breastfeeding (P = .002). We identified 6 individual bacterial genera that were differentially abundant between delivery mode and feeding groups. CONCLUSIONS AND RELEVANCE: The infant intestinal microbiome at approximately 6 weeks of age is significantly associated with both delivery mode and feeding method, and the supplementation of breast milk feeding with formula is associated with a microbiome composition that resembles that of infants who are exclusively formula fed. These results may inform feeding choices and shed light on the mechanisms behind the lifelong health consequences of delivery and infant feeding modalities. Copyright 2016 American Medical Association. All rights reserved.

Maule M.,University of Turin | Scelo G.,International Agency for Research on Cancer IARC | Pastore G.,University of Turin | Brennan P.,International Agency for Research on Cancer IARC | And 22 more authors.
International Journal of Cancer | Year: 2011

Children diagnosed with noncentral nervous system solid cancers (NCNSSC) experience several adverse late effects, including second malignant neoplasm. The aim of our study was to assess the risk of specific second malignancies after a childhood NCNSSC. Diagnosis and follow-up data on 10,988 cases of NCNSSC in children (0-14 years) were obtained from 13 registries. Standardized incidence ratios (SIRs) with 95% confidence intervals (CI) and cumulative incidence of second malignancies were computed. We observed 175 second malignant neoplasms, yielding a SIR of 4.6, 95% CI: 3.9-5.3. When considering second cancers with at least 10 occurrences, highest relative risks were found for second malignant bone tumors (SIR = 26.4, 16.6-40.0), soft tissue sarcomas (SIR = 14.1, 6.7-25.8) and myeloid leukemia (SIR = 12.7, 6.3-22.8). Significant increased risks for all malignancies combined were observed after sympathetic nervous system tumors (SIR = 11.4, 5.2-21.6), retinoblastomas (SIR = 7.3, 5.4-9.8), renal tumors (SIR = 5.7, 3.8-8.0), malignant bone tumors (SIR = 5.6, 3.7-8.2), soft tissue sarcomas (SIR = 4.7, 3.2-6.8), germ-cell, trophoblastic and other gonadal neoplasms (SIR = 2.5, 1.1-4.9), carcinomas and other malignant epithelial neoplasms (SIR = 2.2, 1.4-3.3). The highest risk of a second malignancy of any type occurred 5 to 9 years after NCNSSC (SIR = 9.9, 6.8-13.9). The cumulative incidence of second malignancies 10 years after the first neoplasm was eight times higher among NCNSSC survivors than in the general population, with the absolute difference between observed and expected cumulative incidence still increasing after 50 years of follow-up. Children who survived a NCNSSC experience a large increased risk of developing a new malignancy, even many years after their initial diagnosis. Copyright © 2011 UICC.

Bosetti C.,Instituto Of Ricerche Farmacologiche Mario Negri | Scelo G.,International Agency for Research on Cancer IARC | Chuang S.-C.,International Agency for Research on Cancer IARC | Chuang S.-C.,Imperial College London | And 29 more authors.
International Journal of Cancer | Year: 2011

Scanty data are available on the incidence (i.e., the absolute risk) of second cancers of the head and neck (HN) and its pattern with age. We investigated this issue using data from a multicentric study of 13 population-based cancer registries from Europe, Canada, Australia and Singapore for the years 1943-2000. A total of 99,257 patients had a first primary HN cancer (15,985 tongue, 22,378 mouth, 20,758 pharyngeal, and 40,190 laryngeal cancer), contributing to 489,855 person-years of follow-up. A total of 1,294 of the patients (1.3%) were diagnosed with second HN cancers (342 tongue, 345 mouth, 418 pharynx and 189 larynx). Male incidence rates of first HN cancer steeply increased from 0.68/100,000 at age 30-34 to 46.2/100,000 at age 70-74, and leveled off at older age; female incidence increased from 0.50/100,000 at age 30-34 to 16.5/100,000 at age 80-84. However, age-specific incidence of second HN cancers after a first HN cancer in men was around 200-300/100,000 between age 40-44 and age 70-74 and tended to decline at subsequent ages (150/100,000 at age 80-84); in women, incidence of second HN cancers was around 200-300/100,000 between age 45-49 and 80-84. The patterns of age-specific incidence were consistent for different subsites of second HN cancer and sexes; moreover, they were similar for age-specific incidence of first primary HN cancer in patients who subsequently developed a second HN cancer. The incidence of second HN cancers does not increase with age, but remains constant, or if anything, decreases with advancing age. Copyright © 2010 UICC.

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