Integration of pharmacology, molecular pathology, and population data science to support precision gastrointestinal oncology

Abstract

Precision medicine has a goal of customizing disease prevention and treatment strategies. Under the precision medicine paradigm, each patient has unique pathologic processes resulting from cellular genomic, epigenomic, proteomic, and metabolomic alterations, which are influenced by pharmacological, environmental, microbial, dietary, and lifestyle factors. Hence, to realize the promise of precision medicine, multi-level research methods that can comprehensively analyze many of these variables are needed. In order to address this gap, the integrative field of molecular pathology and population data science (i.e., molecular pathological epidemiology) has been developed to enable such multi-level analyses, especially in gastrointestinal cancer research. Further integration of pharmacology can improve our understanding of drug effects, and inform decision-making of drug use at both the individual and population levels. Such integrative research demonstrated potential benefits of aspirin in colorectal carcinoma with PIK3CA mutations, providing the basis for new clinical trials. Evidence also suggests that HPGD (15-PDGH) expression levels in normal colon and the germline rs6983267 polymorphism that relates to tumor CTNNB1 (β-catenin)/WNT signaling status may predict the efficacy of aspirin for cancer chemoprevention. As immune checkpoint blockade targeting the CD274 (PD-L1)/PDCD1 (PD-1) pathway for microsatellite instability-high (or mismatch repair-deficient) metastatic gastrointestinal or other tumors has become standard of care, potential modifying effects of dietary, lifestyle, microbial, and environmental factors on immunotherapy need to be studied to further optimize treatment strategies. With its broad applicability, our integrative approach can provide insights into the interactive role of medications, exposures, and molecular pathology, and guide the development of precision medicine.

Long‐term use of low‐dose aspirin for cancer prevention: A 10‐year population cohort study in Hong Kong

“…Last but not least, molecular pathological epidemiology (MPE) has emerged in recent years as a powerful approach in investigating relationship between exposures and disease risk. [29][30][31][32] Advances in cancer biology has clearly indicated that development of malignant disease is the result of a complicated interactions and integrations of genomic, epigenomic, proteomic and metabolomic alterations that involves environmental, microbial, dietary, pharmacological and lifestyle factors. In the era of precision oncology, treatment of an individual's cancer should be personalized according to the genetic and environmental factors.…”

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

“…15 Our study has notable strengths including the use of a molecular pathological epidemiology database derived from two U.S. prospective cohort studies with long duration of follow-up. 53,54 Integrated data on tumor molecular characteristics and pathological findings allowed us to comprehensively characterize TIME subtypes of colorectal cancer. Of note, our study population was derived from a large number of cases from hospitals located throughout the U.S., contributing to increased generalizability of our findings.…”

Low‐dose aspirin can reduce colorectal cancer mortality after surgery: A 10‐year follow‐up of 13 528 colorectal cancer patients

“…These are important studies in molecular pathological epidemiology that would shed light on future strategies in prevention and treatment of CRC. 31,32 There are several limitations in this study. Because of the limited amount of information available in this electronic medical record system, there is no clear definition of the disease staging, and hence, we were not sure whether the chemopreventive effects of aspirin were demonstrable in Stage I to III CRC.…”

“…In CRC, the potential benefit of aspirin with PIK3CA mutations, HPGD expression levels in normal colon, and the germline polymorphism that relates to beta‐catenin/WNT signaling pathway may also predict the efficacy of aspirin for cancer chemoprevention. These are important studies in molecular pathological epidemiology that would shed light on future strategies in prevention and treatment of CRC …”