Program Activities and Selected Scientific Reports
The leaders of the Cancer Epidemiology Research Program at Norris Cotton Cancer Center are Carmen Marsit, PhD and Margaret Karagas, PhD. This research program, located at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, is one of six foundational programs at Norris Cotton Cancer Center.
This active research program has monthly meetings where they hear from other members about research findings and host outside speakers on their work related to themes in Cancer Epidemiology. They also sponsor the Cancer Epidemiology Seminar Series. Their program-sponsored Bladder Cancer Focus Group provides opportunities for members and others to discuss common interests in research of bladder cancer. Similarly, Christopher Amos, PhD, who is the Acting Deputy Director of Norris Cotton Cancer Center, has organized the Biostatistics Journal Club for discussions with a high level of specificity. Annually, the members of Cancer Epidemiology gather for a program retreat to discussion ongoing research and to strategize about larger multidisciplinary projects.
Academic life at Dartmouth includes a multitude of opportunities to discuss common scientific interests with others. The annual Integrative Biology Symposium is one such event and in recent years it has focused on obesity, global health, and the micro biome.
Similarly, a number of Dartmouth seminar series are enriched by participation of Cancer Epidemiology members including Genomic Grand Rounds, the Biostatistics Seminar Series, the Pharmacology and Toxicology Seminar Series, the Children’s Environmental Health and Disease Prevention Seminar Series, and the Biological Sciences Department Seminars, among others.
Disease-site specific tumor boards are distinctive at Norris Cotton Cancer Center and the involvement of basic scientists in tumor boards is both important and unusual. An early adopter of this model is Brock Christensen, PhD who is a basic scientist embedded in the Breast Cancer Tumor Board.
Both Jason Moore, PhD and Scott Williams, PhD are organizers of the annual Dartmouth Integrative Biology Symposium. Presenters from Cancer Epidemiology include Richard Rothstein, MD who is also Chief of Surgery, Diane Gilbert-Diamond, and Jennifer Doherty.
The program fosters development of new funding opportunities for example the COBRE Quantitative Biology Institute, COBRE Center for Molecular Epidemiology, the Children’s Environmental Health and Disease Prevention Research Center, and collaborative R01/U01 applications. Recent recruitment to increase the program’s strength include Jennifer Doherty, Olga Gorlova, PhD, Carmen Marsit, Christopher Amos, and Brock Christensen in the theme of population genomics, and both Diane Gilbert-Diamond and Carmen Marsit in the theme of life course epidemiology.
Members teach frequently in Biology at Dartmouth College, the PEMM program, and QBS at Dartmouth’s graduate school of arts and sciences. Their courses are as follows:
Angeline Andrew – Molecular Epidemiology
Brock Christensen – Biostatistics, Molecular Epidemiology
Jennifer Doherty – Epidemiology
Diane Gilbert-Diamond – Biostatistics
Jlang Gui – Biostatistics
Margaret Karagas –Global Health, Epidemiology
Zhigang Li – Biostatistics
Carmen Marsit – Biostatistics, Molecular Epidemiology
Jason Moore – Intro to QBS, Bioinformatics
Judith Rees – Epidemiology/Quantitative Methods
Cancer Epidemiology members serve on major study sections including Linda Titus, PhD, Margaret Karagas and John Baron, MD who have served on the EPIC study section. Marlene Goldman, PhD is a member of the IRAP study section. Currently, Margaret Karagas is a member of the NAS Committee to Review the EPA IRIS on arsenic in drinking water and chaired the Epidemiology Work Group for recent IARC monograph on the Carcinogenicity of some drugs and herbal medicines. Cancer Epidemiology is well-represented at regional, national and international meetings including those held by AACR and MEG including the Frontiers in Cancer Prevention and Molecular Epidemiology Special Conferences, with Jennifer Doherty presenting at the AACR/MEG sponsored Post-GWAS in Molecular Epidemiology conference.
2013 Selected Scientific Progress & Achievements
Drs. Gui, Moore, Williams and Gilbert-Diamond have collaborated on developing methods to utilize their novel model of epistasis for examining quantitative traits (Gui PLoS One, 2013). Drs. Amos, Moore and colleagues have developed pioneering methods to examine gene-gene and gene-environment interactions in the GWAS context (Sohns M Genet Epidemio, 2013). In another methods development, Drs. Marsit, Christensen, Karagas and Andrew are developing methodologies to account for cell subtype variation in epigenome-wide studies (Koestler Epigenetics, 2013).
Dr. Andrew is collaborating with researchers in the New Hampshire colonoscopy registry to examine DNA methylation in pre-neoplastic and neoplastic lesions from individuals undergoing colon cancer screening (Koestler et al Modern Pathology, 2013). Drs. Andrew, Marsit, Moore and Karagas, with the NCCC Pathology Shared Resource (Tsongalis) and Dr. Butterly (Cancer Control) have examined epigenomic profiles of colon adenomas, identifying key differences in DNA methylation profiles between right and left colon polyps which could underlie the distinct clinical consequences observed with these lesions (Koestler Mod Pathol, 2013). Dr. Baron continues to collaborate with investigators in the CEC Program on analyses of large, multi-center trials aimed at understanding potential chemopreventive agents in colorectal carcinogenesis, including aspirin, folate, vitamin D and calcium (Vollset Lancet, 2013).
The Population Epigenomics group also has performed pioneering epigenome-wide association studies relating utero arsenic exposure to altered DNA methylation profiles (Koestler EHP, 2013). The effect of intrauterine/early life exposures on adult onset cancers is an area of growing interest of Program members (Farzan,2013).
Dr. Amos has used genetic fine-mapping techniques to identify regions of genetic variability associated with lung cancer risk with histologic specificity in African Americans (Walsh CEBP, 2013).
Studies of skin, as an emerging public health issue and a model for carcinogen discovery continue as a focus within the program. The non-melanoma skin cancer incidence and case control study, led by Drs. Karagas, Rees, and colleagues; has been a productive inquiry. Their work led to the identification of an association between non-melanoma skin cancer and photosensitizing drug use (Robinson et al, 2013), and with genus beta human papilloma viruses as a risk factor (Farzan et al, 2013).
2012 Selected Scientific Accomplishments
- Developed novel murine transgenic and transplantable lung cancer models that have proven useful to study lung cancer biology, therapy, and prevention. These models uncovered microRNA-31 and CDK2 (and induced anaphase catastrophe) as molecular pharmacologic targets to reduce lung cancers, as reviewed (Liu X, 2011 and Galimberti F, 2011).
- Liu X, Sempere LF, Guo Y, Korc M, Kauppinen S, Freemantle SJ, Dmitrovsky E (2011). Involvement of microRNAs in lung cancer biology and therapy. Translational Res:J Lab Clin Med 157(4):200-208. PMCID: PMC3072599 [Available on 2012/4/1]
- Completed a Phase II trial and proof-of-principle trial targeting cyclin D1 with erlotinib and bexarotene. These trials found that the two drugs conferred a survival advantage and activity against lung cancers even when ras mutations were present (Dragnev KH, 2011). This publication was accompanied with an editorial and a report by a team at MD Anderson that independently confirmed our findings in an active arm of the BATTLE Trial.
- Dragnev KH, Ma T, Cyrus J, Galimberti F, Memoli V, Busch AM, Tsongalis GJ, Seltzer M, Johnstone D, Erkmen CP, Nugent W, Tsongalis GJ, Liu X, Freemantle SJ, Kurie JM, Waxman S, Dmitrovsky E (2011). Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models. Cancer Prev Res (Phila) 4(6):818-828. PMCID: PMC3108499
- Drs. Jiang Gui, Moore, Andrew, Marsit and Karagas published new methods of detecting interactions in high-dimensional data to assess patient prognosis in Human Genetics.
- Gui J, Moore JH, Kelsey KT, Marsit CJ, Karagas MR, Andrew AS (2011b). A novel survival multifactor dimensionality reduction method for detecting gene-gene interactions with application to bladder cancer prognosis. Hum Genet 129(1):101-110.
- A pooled analysis of folate chemoprevention trials recently published suggests no clear effects of folate supplementation on colorectal neoplasia (Figueiredo J, 2011b).
- Figueiredo JC, Mott LA, Giovannucci E, Wu K, Cole B, Grainge MJ, Logan RF, Baron JA (2011b). Folic acid and prevention of colorectal adenomas: A combined analysis of randomized clinical trials. Int J Cancer 129(1):192-203.
- In a report published in the past year, serum salicylate did not relate to risk of colorectal polyps among participants in the calcium intervention trial, but levels may have been too low to detect an association (Shaukat A, 2011).
- Shaukat A, Grau MV, Church TR, Baxter G, Barry EL, Summers R, Sandler RS, Baron JA (2011). Serum salicylate levels and risk of recurrent of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 20(4):679-682.
- This past year, several findings emerged from a collaborative study, including on the role of polymorphisms in mismatch repair genes (Parry S, 2011).
- Parry S, Win AK, Parry B, Macrae FA, Gurrin LC, Church JM, Baron JA, Giles GG, Leggett BA, Winship I, Lipton L, Young GP, Young JP, Lodge CJ, Southey MC, Newcomb PA, Le Marchand L, Haile RW, Lindor NM, Gallinger S, Hopper JL, Jenkins MA (2011). Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: The advantage of more extensive colon surgery. Gut 60(7):950-957. PMCID: PMC
- Discovered that abnormalities of the Hh signaling pathway are frequent in non-small-cell lung cancers (Singh S, 2011).
- Singh S, Wang Z, Liang Fei D, Black KE, Goetz JA, Tokhunts R, Giambelli C, Rodriguez-Blanco J, Long J, Lee E, Briegel KJ, Bejarano PA, Dmitrovsky E, Capobianco AJ, Robbins DJ (2011). Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity. Cancer Res 71(13):4454-4463.
- Using a cancer gene methylation array, several methodological and cancer-specific findings have emerged, in particular the importance of examining the patterns of DNA methylation alterations in the pathogenesis and progression of human malignancies (Marsit C, 2011).
- Marsit CJ, Koestler DC, Christensen BC, Karagas MR, Houseman EA, Kelsey KT (2011). DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer. J Clin Oncol 29(9):1133-1139. PMCID: PMC3083868 [Available on 2012/3/20]
- Drs. Baron, Onega (CC) and Allen Dietrich (former CC) have established a New Hampshire colonoscopy registry (Greene et al., 2011).
- Greene MA, Butterly LF, Goodrich M, Onega T, Baron JA, Lieberman DA, Dietrich AJ, Srivastava A (2011). Matching colonoscopy and pathology data in population-based registries: Development of a novel algorithm and the initial experience of the New Hampshire Colonoscopy Registry. Gastrointest Endosc 74(2):334-340. PMCID: PMC3148344 [Available on 2012/8/1]
- Revealed the importance of the TP53 status of the tumor on risk factors, such as use of NSAIDs (Torti D, 2011)
- Torti DC, Christensen BC, Storm CA, Fortuny J, Perry AE, Zens MS, Stukel T, Spencer SK, Nelson HH, Karagas MR (2011). Analgesic and nonsteroidal anti-inflammatory use in relation to nonmelanoma skin cancer: A population-based case-control study. J Am Acad Dermatol 65(2):304-312. PMCID: PMC3140678 [Available on 2012/8/1]
- Importance of TP53 for potential susceptibility loci (Almquist L, 2011).
- Almquist LM, Karagas MR, Christensen BC, Welsh MM, Perry AE, Storm CA, Nelson HH (2011). The role of TP53 and MDM2 polymorphisms in TP53 mutagenesis and risk of non-melanoma skin cancer. Carcinogenesis 32(3):327-330. PMCID: PMC33105583 [Available on 2012/3/1]
- Elucidated the role of sex hormone-related factors, diabetes, and specific aspects of diet on bladder cancer incidence (Brinkman M, 2011; MacKenzie T, 2011; Dietrich K, 2011).
- Brinkman MT, Karagas MR, Zens MS, Schned AR, Reulen RC, Zeegers MP (2011). Intake of alpha-linolenic acid and other fatty acids in relation to the risk of bladder cancer: Results from the New Hampshire case-control study. Br J Nutr 1-8.
- Dietrich K, Demidenko E, Schned A, Zens MS, Heaney J, Karagas MR (2011). Parity, early menopause and the incidence of bladder cancer in women: A case-control study and metaanalysis. Eur J Cancer 47(4):592-599. PMCID: PMC3042804 [Available on 2012/3/1]
- Mackenzie T, Zens MS, Ferrara A, Schned A, Karagas MR (2011). Diabetes and risk of bladder cancer: Evidence from a case-control study in New England. Cancer 117(7):1552-1556. PMCID: PMC3117102 [Available on 2012/5/8]
- Using MDR and other approaches for examining combinations of effects, we found that skin type, IL10, IL4, IL4R, and possibly TNFR2 are associated with skin cancer susceptibility (Welsh M, 2011).
- Welsh MM, Karagas MR, Kuriger JK, Houseman A, Spencer SK, Perry AE, Nelson HH (2011). Genetic determinants of UV-susceptibility in non-melanoma skin cancer. PLoS One 6(7):e20019. PMCID: PMC3132750
- Continued studies of the epidemiology of melanoma, pooling data with studies across the world, exploring pathways of melanocyte carcinogenesis (Olsen C, 2011).
- Olsen CM, Zens MS, Green AC, Stukel TA, Holman CD, Mack T, Elwood JM, Holly EA, Sacerdote C, Gallagher R, Swerdlow AJ, Armstrong BK, Rosso S, Kirkpatrick C, Zanetti R, Bishop JN, Bataille V, Chang YM, Mackie R, Osterlind A, Berwick M, Karagas MR, Whiteman DC (2011). Biologic markers of sun exposure and melanoma risk in women: Pooled casecontrol analysis. Int J Cancer 129(3):713-723. PMCID: PMC3035752 [Available on 2012/3/20]
- A recent analysis indicates an increased risk of pre-term delivery, being small-for-gestational age, and possibly early-onset menarche among DES-exposed women (Hatch E, 2011).
- Hatch EE, Troisi R, Wise LA, Titus-Ernstoff L, Hyer M, Palmer JR, Strohsnitter WC, Robboy SJ, Anderson D, Kaufman R, Adam E, Hoover RN (2011). Pre-term birth, fetal growth, and age at menarche among women exposed prenatally to diethylstilbestrol (DES). Reprod Toxicol 31(2):151-157. PMCID: PMC3057340 [Available on 2012/2/1]
- Recent work also has identified the timing of pregnancy in relation to lobular breast cancer (Newcomb P, 2011)
- Newcomb PA, Trentham-Dietz A, Hampton JM, Egan KM, Titus-Ernstoff L, Warren Andersen S, Greenberg ER, Willett WCMD (2011). Late age at first full term birth is strongly associated with lobular breast cancer. Cancer 117(9):1946-1956. PMCID: PMC3117094 [Available on 2012/5/10]
- Multiple factors identified that influence breast cancer survival, including social network and fat intake (Beasley J, 2010, 2011).
- Beasley JM, Newcomb PA, Trentham-Dietz A, Hampton JM, Bersch AJ, Passarelli MN, Holick CN, Titus-Ernstoff L, Egan KM, Holmes MD, Willett WC (2011). Post-diagnosis dietary factors and survival after invasive breast cancer. Breast Cancer Res Treat 128(1):229-236.
- Breast cancer survival risk factors by specific histologic types (Merritt, 2012; Pearce, 2012; Warren Andersen, 2011).
- Warren Andersen S, Newcomb PA, Hampton JM, Titus-Ernstoff L, Egan KM, Trentham-Dietz A (2011, In press). Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis. Breast Cancer Res Treat.
- Breast cancer association with a functional SNP at 6Q25.1 (Cai Q, 2011),
- Cai Q, Wen W, Qu S, Li G, Egan KM, Chen K, Deming SL, Shen H, Shen CY, Gammon MD, Blot WJ, Matsuo K, Haiman CA, Khoo US, Iwasaki M, Santella RM, Zhang L, Fair AM, Hu Z, Wu PE, Signorello LB, Titus-Ernstoff L, Tajima K, Henderson BE, Chan KY, Kasuga Y, Newcomb PA, Zheng H, Cui Y, Wang F, Shieh YL, Iwata H, Le Marchand L, Chan SY, Shrubsole MJ, Trentham-Dietz A, Tsugane S, Garcia-Closas M, Long J, Li C, Shi J, Huang B, Xiang YB, Gao YT, Lu W, Shu XO, Zheng W (2011). Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of Chinese, Japanese, and European Ancestry. Cancer Res 71(4):1344-1355. PMCID: PMC3083305 [Available on 2012/2/15]
- Published new approaches for assessing gene-gene and gene-environment interactions with covariate adjustment and for application to survival data (Gui J, 2010; 2011a).
- Gui J, Andrew AS, Andrews P, Nelson HM, Kelsey KT, Karagas MR, Moore JH (2011a). A robust multifactor dimensionality reduction method for detecting gene-gene interactions with application to the genetic analysis of bladder cancer susceptibility. Ann Hum Genet 75(1):20-28. PMCID: PMC3057873 [Available on 2012/1/1]
- New analytic tools to investigate interactions with data mining (e.g., Urbach D, 2011),
- Urbach D, Moore JH (2011a). Data mining and the evolution of biological complexity. BioData mining 4:7. PMCID: PMC3083376
- Urbach D, Moore JH (2011b). Mining beyond the exome. BioData mining 4(1):14. PMCID: PMC3144005