NCI’s Division of Cancer Epidemiology and Genetics 4/21/2017 NCI’s Division of Cancer Epidemiology and Genetics Neil Caporaso, M.D. Chief, Genetic Epidemiology Branch DCEG, NCI www.dceg.cancer.gov National Cancer Institute

Division of Cancer Epidemiology and Genetics 4/21/2017 Division of Cancer Epidemiology and Genetics Discovering the Causes of Cancer national and international intramural, population-based research Mission: * broad-based, high quality, high impact research to uncover causes of cancer and means of its prevention. * national and international perspective. * develop research resources and strategic partnerships in molecular epidemiology across NCI, NIH and the research global community * train the next generation of scientists in cancer epidemiology and related areas. National Cancer Institute

National Cancer Institute 69 Principal Investigators 4/21/2017 National Cancer Institute Intramural Divisions Extramural Divisions DCEG CCR 8 Branches/1 Lab 69 Principal Investigators ~205 Investigators National Cancer Institute

National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics Find the CAUSE! Genetic Epidemiology Branch Other Branches focus on Nutrition, Hormones, Infection, Occupation, Statistics, Radiation

Why have an intramural program? Example 1 In the 1980/90s many groups independently reported that normal patients had excess clonal B lymphocytes in the blood. Each investigator gave it a different name Benign monoclonal B-cell lymphocytosis (BMBCL) Han 1984 Idiopathic persistent lymphocytosis Bassan 1988 B-monoclonal lymphocytosis undetermined significance Garcia 1989 Smoldering CLL Montserrat 1988 B-cell monoclonal lymphocytosis (BCML) Marti 1993 Sub-clinical BCLL B-cell monoclonal lymphocytosis Maiese 1997 CD5 negative BMLUS Wang 2002 CLL-like immunophenotype (CLUS) Rawstron 2 B cell clones where observed and reported by many investigators including our group but the literature was chaotic. There was a bewildering list of terms and definitions that all referred to diverse entities The challenges were clear There was no systematic approach to identification of the entity, no uniform diagnostic criteria, the nomenclature was unstable, the distinction from CLL uncertain, and each group pursued their own vision …. I felt this was an important issue and one where my position in the intramural program could be helpful I organized a series of meetings under the rubric of the IFCLL- The International And we crafted a consensus which was adopted by the International Community in 2005 And had the desired result Given a stable nomenclature Many investigators began to publish observations

Why have an intramural program? 2 2003 2005 2007 2010 B cell clones where observed and reported by many investigators including our group but the literature was chaotic. There was a bewildering list of terms and definitions that all referred to diverse entities The challenges were clear There was no systematic approach to identification of the entity, no uniform diagnostic criteria, the nomenclature was unstable, the distinction from CLL uncertain, and each group pursued their own vision …. I felt this was an important issue and one where my position in the intramural program could be helpful I organized a series of meetings under the rubric of the IFCLL- The International And we crafted a consensus which was adopted by the International Community in 2005 And had the desired result Given a stable nomenclature Many investigators began to publish observations Monoclonal B Cell Lymphocytosis (MBL)

Family Studies were not popular Example 2 Family Studies were not popular Early ideas in human genetics: If it’s genetic it’s rare If its genetic it’s only in families If it’s genetic you can’t change it If it’s genetic there is no treatment If it’s genetic the environment doesn’t matter ALL THESE ASSUMPTIONS WERE WRONG

Family studies by our group….. While our eyes are to the future - It its important to note some historic roots of GEB (that help our work today) Some of the earliest families were identified by Dr. Fraumeni, the head of our Division Who identified an early CLL kindred. Another example of a landmark study was the identification of dysplastic nevi in melanoma kindreds. I note this to emphasize that there is a continuity to our investigations within the Division that amplifies our scientific reach. EXAMPLE 1- We see families repeatedly- follow them over time, and have the opportunity to apply new technologies EXAMPLE 2- Although Mark and Peggys discovery was years ago- the lesson that families are a good place to look for precursors was not lost- and we discovered them in CLL. Today GEB…..

Family studies by our group….. dysplastic nevus While our eyes are to the future - It its important to note some historic roots of GEB (that help our work today) Some of the earliest families were identified by Dr. Fraumeni, the head of our Division Who identified an early CLL kindred. Another example of a landmark study was the identification of dysplastic nevi in melanoma kindreds. I note this to emphasize that there is a continuity to our investigations within the Division that amplifies our scientific reach. EXAMPLE 1- We see families repeatedly- follow them over time, and have the opportunity to apply new technologies EXAMPLE 2- Although Mark and Peggys discovery was years ago- the lesson that families are a good place to look for precursors was not lost- and we discovered them in CLL. Today GEB…..

Most Cancer is due to the Environment Dramatic differences in cancer rates by geography and over time are only compatible with extrinsic environmental causes Established by a vast body of descriptive, ecological, and analytical epidemiology Kindreds are quite impressive Case-control studies consistently identify increased risks in relatives of cases compared to matched realtives of controls Segregation is consistent with gene effect Population databases show familial aggregation consistent with genetics Twin studies provide mixed evidence- I’ll show you what I mean in a moment Animal models identify both susceptibility and resistace loci- some of the genes are similar or identical with genes that are observed to be mutated in human cancer Finally, as we’ll see, there are many biologically plausible candidates

Per-Capita Consumption of Different Forms of Tobacco in The U. S I would love to say that improved incidence or treatment have results from our molecular epi studies over the last decade. In fact, what improvements have occurred –and here you see the per capita drop in cigarette consumption in the United States Deriving from epi work of the mid century And the Surgeon Generals Report Have resulted from TOBACCO Control- and legislation made possible in part by epid studies showing the health consequences of 2nd hand smoke- resulting in Clean Air Legislation- that directly and indirectly helps people quit smoking As you all know, lung cancer incidence and mortality rose through this period Because of the 30 year lag- But incidence curves have have now rolled over Decades in the 1900s Data Source USDA

Lung cancer rate drops after smoking cessation

Why here? When the global variation in cancer incidence became evident, we wondered what was happening close to home. When analyzed by region and state, the patterns in the U.S. were not very remarkable, but when the rates at the county level were displayed on computer-generated maps, patterns were uncovered that indicated enemy action and an opportunity to learn more about environmental cancer. For lung cancer, the elevated rates were—tended—that are shown here in red tended to cluster along the seaboard, with the highest rates in a band of counties along the southeast Atlantic coast. There were also some intriguing outliers with elevated rates scattered in western areas of the country, as seen here in Montana, which I’ll come back to.

Copper Smelter, Montana Another environmental hazard was found to explain the high rates of lung cancer in a county in Montana where workers in this particular copper smelter had an overall 3-fold risk of lung cancer rising to 8-fold among those most heavily exposed to inorganic arsenic. In addition, a study of lung cancer in several areas of the country with arsenic-emitting smelters revealed elevated risks among both men and women with neighborhood exposures to arsenic, even after taking occupation and smoking into account. These studies led to new standards by OSHA and EPA to curtail airborne exposures to arsenic. Copper Smelter, Montana

Traditional epidemiology Exposure Disease Tobacco Lung Cancer There are 4 types of insight one may get from investigation of tumor markers studies of the marker itself- for instance an investigation of the relation of p53 sequence mutations in relation to p53 protein detection studies in relation to exposure studies in relation to genes- both inherited variation and expression studies in relation to clinical and outcome. I will note that each of these areas has been implicitly recognized as both crucial and an emerging opportunity by the Institute By Molecular Signature. CGAP, and the Director’s Challenge to develop a molecular diagnosis of tumors. I would offer the general observation that these efforts have not always 15

Molecular epidemiology EBE ASF ED D exposure internal dose early biological effect altered structure or function early disease disease There are 4 types of insight one may get from investigation of tumor markers studies of the marker itself- for instance an investigation of the relation of p53 sequence mutations in relation to p53 protein detection studies in relation to exposure studies in relation to genes- both inherited variation and expression studies in relation to clinical and outcome. I will note that each of these areas has been implicitly recognized as both crucial and an emerging opportunity by the Institute By Molecular Signature. CGAP, and the Director’s Challenge to develop a molecular diagnosis of tumors. I would offer the general observation that these efforts have not always Adding biomarkers allows us to investigate genes and mechanisms 16

Integrative epidemiology B E ID EBE ASF ED D exposure internal dose early biological effect altered structure or function early disease disease There are 4 types of insight one may get from investigation of tumor markers studies of the marker itself- for instance an investigation of the relation of p53 sequence mutations in relation to p53 protein detection studies in relation to exposure studies in relation to genes- both inherited variation and expression studies in relation to clinical and outcome. I will note that each of these areas has been implicitly recognized as both crucial and an emerging opportunity by the Institute By Molecular Signature. CGAP, and the Director’s Challenge to develop a molecular diagnosis of tumors. I would offer the general observation that these efforts have not always Outcome Behavior

Areas of Investigation 4/21/2017 DCEG Areas of Investigation Lifestyle risk factors (hormonal and nutritional exposures) Environmental and occupational exposures Infectious agents Radiation Statistics and methods development Genetic predisposition Genome-wide association studies and Next-gen sequencing National Cancer Institute

National Cancer Institute 4/21/2017 DCEG Staff and Trainee Profile ~25 summer students ~100 postbaccalaureate, predoctoral, postdoctoral and clinical trainees 36 staff scientist/staff clinicians 26 tenure-track investigators 43 senior investigators National Cancer Institute

DCEG Selected Discoveries Hormone replacement and breast/ovarian cancer Benzene and formaldehyde and leukemia/lymphoma Role of p53 gene in Li-Fraumeni syndrome Gail breast cancer risk model Cancer risk among atomic bomb survivors No link between breast implants – breast cancer, cell phones – brain cancer, or power-lines – childhood leukemia

Personal view- Our Branch Selected Discoveries (GEB/2014) Largest study of genes and lung cancer POT1- gene associated with familial melanoma Methylome and lung cancer The “Time to First Cigarette” is a critical determinant of lung cancer risk

What we look for in early career investigators DCEG What we look for in early career investigators Great science: important work, published in top-notch journals Good quality work: strong rationale and research methods Depth and breath of scientific knowledge Evidence of creativity, innovation, and originality – person is moving the field forward Collaborative, interdisciplinary spirit Capacity for independence and leadership Ability and enthusiasm to mentor

MOVIVATION and CHARACTER Personal view What we look for in early career investigators 3 qualities TRAINING MOVIVATION and CHARACTER HARD WORK