Loic Le Marchand, MD, PhD
- Professor and Full Member
University of Hawaii Cancer Center
- Clinical Professor
John A. Burns School of Medicine, University of Hawaii at Manoa
- Graduate Faculty
Biomedical Sciences Interdisciplinary Graduate Program and Cell and Molecular Biology Program, John A. Burns School of Medicine, University of Hawaii at Manoa Department of Food Science and Human Nutrition, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa
University of Rennes, France
- MPH (Epidemiology)
University of Hawaii
- PhD, Epidemiology/Biostatistics
University of Hawaii at Manoa
- Preventive Medicine Residency
University of Hawaii at Manoa
- French Medical License and Certification in Public Health
My research Investigates the interactions between genetic and lifestyle factors responsible for the cancer risk differences that exist among ethnic/racial groups in Hawaii and California, with the goal of advancing our understanding of the causes, mechanisms and prevention of cancer. This multidisciplinary effort is focusing on three common cancers (colorectal, lung and breast) and the two main causes of cancer (smoking and obesity).
Early work showed that migrants experienced a major shift in cancer rates in one or two generations toward the rates of their adoptive country, suggesting that the environment (i.e., lifestyle), and not the genetic make-up of the individual, plays a predominant role in determining cancer risk. However, lifestyle clearly does not account for all of the variability in cancer risk that exists across individuals and populations. Indeed, it is generally accepted that most cancers result from the combined effects of environmental factors and common inherited susceptibilities. However, these genetic factors and their interactions with environmental exposures remain largely unknown. My group has identified several "epidemiological anomalies" in which there is a large gap between the expected cancer risk profile of a population, based on lifestyle exposures, and the observed risk. These anomalies provide unique opportunities to identify new risk factors and/or potentially important gene-environment interactions.
To investigate these intriguing observations, I focused, starting in the early 1990's, on candidate genes that may modify the risk associated with lifestyle exposures (smoking, dietary constituents, obesity and medications). This NCI- and NHGRI-funded research has relied on cross-sectional, case-control, cohort and intervention studies and a Family Registry. It also relies heavily on public information available on the human genome and, particularly, the small percentage of DNA bases that differ across individuals and are responsible for phenotypic variation. This research first focused on functional genetic polymorphisms affecting carcinogen bioactivation, DNA synthesis and repair, cell proliferation, and angiogenesis. In the past five years, it has included broader investigations, such as pathway-driven and whole-genome association studies. Particular attention is given to replication, generalizability and gene-environment interactions when assessing association with disease. Molecular studies, some using microarrays, are also conducted to characterize the effects of the risk variants on gene expression, biomarkers or intermediate phenotypes.
For example, we showed that the Japanese who migrated to Hawaii have a particular susceptibility to the effect of the western lifestyle on colorectal cancer risk, as their rates increased as early as in the first generation of migrants to surpass those of whites. The same phenomenon has taken place in Japan during the last few decades where colorectal cancer rates are now among the highest in the world. We have conducted a number of studies suggesting that exposure to chemical carcinogens through a high red meat diet and smoking, combined with a genetically-derived greater ability to bioactivate these carcinogens, may contribute to the extremely high Japanese rates for this disease. We have now expanded this research by conducting a GWAS of colorectal cancer in Japanese and African Americans, the two groups with the highest rates for this cancer in the U.S. In collaboration with a well established chemist (Dr. Robert Turesky), we have conducted feeding studies to validate hair PhIP measurement as a biomarker of long-term heterocyclic amine (HAA) exposure that could be used in cohort studies to confirm the association of HAAs with cancer risk.
We also showed that there exist large ethnic/racial differences in the risk of lung cancer associated with smoking. We first made these observations in a case-control study, then, replicated and expanded them with our USC colleagues in the Mutiethnic Cohort (MEC) Study. We followed up this observation in an R01 and showed that the lower lung cancer risk of Japanese for a given lifetime smoking exposure is due to their slower nicotine metabolism, leading them to draw less nicotine and, as the result, less carcinogens, from each cigarette. We are currently expanding these findings in a P01 with colleagues at the University of Minnesota through a GWAS of biomarkers assessing the metabolisms of nicotine and various tobacco carcinogens in smokers.
Similarly, we showed in the MEC that BMI carries different risks for breast and colorectal cancer across ethnic groups. We are following up on these observations in a P01 on obesity and cancer using DXA and abdominal MRI to characterize specific sub-phenotypes of obesity (e.g., visceral fat) across ethnic groups, and to study their determinants and their association with breast and colorectal cancers.
The MEC has become an essential resource for my work. Established by Dr. Kolonel in Hawaii and Dr. Henderson at USC, this cohort study collected detailed information on diet and other risk factors from over 215,000 men and women residing in Hawaii and California between 1993 and 1996 and has followed them for incident cancer occurrences. The studies based on the self-reported dietary intake information have been extended to study genetics and nutritional biomarkers through the establishment of a biorepository on a large subset (N=70,000) of the cohort. I have played a leadership role in the MEC for a number of years, in particular in the establishment and use of the biorepository. As one of the three multiple PIs of the recently awarded UM1 grant that supports the maintenance of the MEC, my goals are to preserve and enhance the quality and uniqueness of this resource, as well as to optimize its use to address innovative questions that are particularly relevant to understanding and correcting cancer disparities in these populations.
- Wang Hâ€¦Le Marchand L. (2014). Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. Nat Commun. 2014 Aug 8;5:4613. doi: 10.1038/ncomms5613. This is a modified citation.
- Park SLâ€¦Le Marchand L. (2014). Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia. J Natl Cancer Inst. 2014 Apr 1;106(4):dju061. doi: 10.1093/jnci/dju061. Epub 2014 Mar 28. This is a modified citation.
- Cheng Iâ€¦Le Marchand* L. (2013). Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia. Gut. 2013 Aug 9. doi: 10.1136/gutjnl-2013-305189. [Epub ahead of print] *Co-senior author. This is a modified citation.
- Wang Hâ€¦Le Marchand L. (2013). Fine-mapping of Genome-wide Association Study-identified Risk Loci for Colorectal Cancer in African Americans. Hum Mol Genet. 2013 Jul 12. [Epub ahead of print]. This is a modified citation.
- Park LSâ€¦Le Marchand L. (2013). Association of the FTO Obesity Risk Variant rs8050136 With Percent Energy Intake from Fat in Multiple Ethnic/Racial Populations: The PAGE Study. Am J Epidemiol. 2013 Jul 2. [Epub ahead of print]. This is a modified citation.
Publication list via PubMed
- L. Le Marchand, C. Henderson, L. Wilkens, MPIs
UM1 CA164973, National Cancer Institute
"Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study"
- L. Le Marchand, PI
P01 CA169530, National Cancer Institute
"Obesity, Body Fat Distribution and Cancer Risk in the Multiethnic Cohort"
- L. Le Marchand, PI of subcontract, (Haile/Lindor/Jenkins, MPIs)
U01 CA167551, National Cancer Institute
"The Colon Cancer Family Registry Cohort"
- C. Haiman/L. Le Marchand, MPIs
National Human Genome Research Institute
"Epidemiology of Putative Causal Variants in the Multiethnic Cohort"
- L. Le Marchand, PI
1R01CA126895, National Cancer Institute
"Whole Genome Scan for Modifier Genes in Colorectal Cancer"
- L. Le Marchand, Project Leader, (Hecht, Universityy of Minnesota, PI)
P01 CA138338, National Cancer Institute
"Mechanisms of Ethnic Differences in Lung Cancer due to Cigarette Smoking," Project 1: "Multiethnic Genome Scan of Metabolic Phenotypes"
2009 â€“ 2015
- Amos (U. of Texas), Le Marchand, Plass, You, Multiple PIs
1U19 CA148127, National Cancer Institute
"Transdisciplinary Research in Cancer of the Lung (TRICL)"
2010 â€“ 2015
- L. Le Marchand, PI
RFA09/149, World Cancer Research Fund International
"Validation of the Hair as a Tissue to Biomonitor PhIP, a Carcinogenic Heterocyclic Aromatic Amine"
2010 â€“ 2014