1. 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
National Cancer Institute

2. 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

3. 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

4. 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

5. 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

6. Why have an intramural program?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
Monoclonal B Cell Lymphocytosis (MBL)

7. 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

8. 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…..

9. 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…..

10. 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

11. 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

12. Lung cancer rate drops after smoking cessation

13. 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.

14. 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

15. 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

16. 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

17. Integrative epidemiologyB 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

18. 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

19. 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

20. 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

21. 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

22. 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

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