Research Focus

Dr. Le Marchand has conducted research on lifestyle and genetic risk factors for cancer of the lung, breast and colorectum with uninterrupted NCI funding since 1987. His particular focus of research is the role of biological and environmental factors in the etiology and progression of cancer, especially in regard to explaining ethnic/racial differences in cancer risk and survival. He has conducted cross-sectional, case-control, cohort and intervention studies in Hawaiʻi and is the founder of the Hawaiʻi Colorectal Cancer Family Registry. Since 2012, he has been the Contact PI of the Multiethnic Cohort (MEC) Study.

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 individual's genetic make-up, plays a predominant role in determining cancer risk. However, lifestyle clearly does not account for all of the variability in cancer risk observed across individuals and populations. Indeed, it is generally accepted that most cancers result from the combined effects of the environment and genetics. 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 have provided unique opportunities to identify new risk factors and/or potentially important gene-environment interactions.

Colorectal Cancer (CRC): We showed that Japanese who migrated to Hawaiʻi have a particular susceptibility to the effect of the western lifestyle on CRC 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 CRC rates are now among the highest in the world. We have conducted a number of studies suggesting that exposure to chemical carcinogens, especially heterocyclic aromatic amines (HAA), 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 expanded this research by conducting a GWAS of CRC in Japanese and African Americans, the two groups with the highest rates for this cancer in the U.S. We have identified several new risk variants for this cancer and confirmed the modifying effect of NAT2 on the red meat-CRC association. We have also developed long-term biomarkers of HAA exposure, working with Dr. Robert Turesky (University of Minnesota). We have now turned to the role of visceral fat and its metabolic effects as another reason for the high rates of CRC in Japanese Americans.

Obesity: We showed in the Multiethnic Cohort that body mass index (BMI) carries different risks for cancer across ethnic groups. The effect of BMI on breast cancer risk was stronger and observed at a lower level of body fatness in Japanese than in the other groups. This observation led us to hypothesize that visceral fat carries a greater cancer risk than sub-cutaneous fat, as it does for certain risk factors (e.g., diabetes, early menarche). This and a similar observation for colorectal and liver cancers were the premise for our P01 (CA168530) in which 1,861 healthy MEC participants (median age: 69 years) were recruited back to undergo a whole-body DXA and abdominal MRI and anthropometric measurements. Visceral (VAT) and liver fat, adjusted for total adiposity, showed major differences by race and was highest among Japanese Americans, lowest among African Americans, and intermediate among Native Hawaiians, Latinos, and whites. These findings are highly significant since VAT and liver fat carry a higher metabolic risk than sub-cutaneous fat and peripheral fat. We have developed a set of blood biomarkers, which, when added to a model with age, sex, race and BMI, significantly improves the prediction of ectopic fat, with AUROC of 0.93-0.97 for visceral obesity (≥150 cm²) and 0.83-0.93 for non-alcoholic fatty liver disease (NAFLD; ≥5% liver fat) across ethnic groups. Applying the VAT prediction score by measuring these biomarkers in the pre-diagnostic samples in MEC, we were able to confirm the P01’s central hypothesis that the score was associated with risks of breast and colorectal cancers independently of BMI and other risk factors and, possibly, with colorectal cancer in Japanese. We also developed a robust methodology to sample the fecal microbiome in large epidemiological studies and demonstrated that it is stable in individuals over multiple years. We described associations of specific genera and imputed microbial functions with total adiposity and liver fat, and with race/ethnicity. We also observed associations between diet quality indices, including the Mediterranean Diet Score, with lower levels of visceral and liver fat. Following up on our observations, we have developed an intervention using intermittent energy restriction and the Mediterranean diet to reduce VAT and liver fat.

Lung Cancer: 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 MEC. 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 have confirmed and expanded these findings in a P01 (CA138338) with University of Minnesota colleagues through a GWAS of biomarkers assessing the metabolisms of nicotine and various tobacco carcinogens in smokers. In particular, we showed for the first time that the same GWAS hits associated with a metabolic phenotype (CYP2A6) were also associated with cancer risk.