Why do people with certain inherited mutations have higher cancer risks, even at a young age? What can they teach us about the early drivers of cancer development, including in people not born with these mutations?

These “hereditary cancers”, caused by heterozygous loss-of-function mutations in tumor suppressor genes, impact multiple generations, and better prevention strategies are sorely needed. Emerging evidence from us and others indicates that this cancer predisposition cannot be fully explained by the prevailing “two-hit” hypothesis (i.e., carrying one instead of two copies of a protective gene simply increases a cell’s risk of completely losing the gene to suppress malignant transformation). Rather, the heterozygous state itself can cause cellular and molecular abnormalities that substantially elevate cancer risk, independent of full gene loss. Importantly, these abnormalities can also reveal the very early events that promote non-hereditary cancer formation.

Our lab investigates the causes and consequences of these heterozygosity-driven abnormalities (“gene-haploinsufficiency effects”) on hereditary cancer development and explores opportunities for early disease intervention. Insights from these studies can also shed light on the biology and early interception opportunities in non-hereditary cancers.

We combine genetically engineered mouse models, organoid cultures, and advanced omics analyses to study cancer development in a tractable and physiological manner. Our long-term goal is to build a unifying paradigm of hereditary cancers, with shared principles and disease-specific mechanisms.