WashU: Study sheds light on how inherited cancer mutations drive tumor growth

Most cancer genome studies have focused on mutations in the tumor itself and how such gene variants allow a tumor to grow unchecked. A new study, led by researchers at Washington University School of Medicine in St. Louis, takes a deep dive into inherited cancer mutations measured in a healthy blood sample and reports how those mutations might take a toll on the body’s cells starting at birth, perhaps predisposing a person to develop cancers at various stages of life.

The authors analyzed the inherited genomes of more than 1,000 cancer patients and determined how inherited mutations — also known as germline variants — result in malfunctioning proteins, which in turn can impair physiological activities. The findings have implications for determining an individual’s inherited cancer risk and informing potential new strategies for prevention, early detection and treatment.

The study appears April 14 in the journal Cell.

“This is important foundational work for the field,” said senior author Li Ding, the David English Smith Distinguished Professor of Medicine at WashU Medicine. “We need to know how the germline variants — rare or common — potentially impact the protein machinery that makes our bodies work and what those impacts might mean for cancer development over the lifespan.”

The study represents a key milestone in the work of the Clinical Proteomic Tumor Analysis Consortium, a nationwide effort supported by the National Cancer Institute of the National Institutes of Health (NIH) that aims to define the roles of all cellular proteins involved in cancer development and progression. Everyone is born with germline variants — some consequential, some inconsequential, and many uncertain — and over the lifespan, different tissues pick up their own mutations. Tumors almost always have a set of new mutations that has been the focus of most clinical research. In this new study, the focus is on the inherited germline variants, rather than those acquired later.

Physicians can offer people with certain inherited mutations — such as those in two BRCA genes, which are known to increase breast cancer risk — options to reduce their risk of developing cancer. These interventions include more frequent breast cancer screening, preventive chemotherapy and surgeries. The new study builds on the utility of knowing cancer risks generated by germline mutations by analyzing the genomes of healthy cells from more than 1,000 cancer patients.

The team, co-led by first author Fernanda Martins Rodrigues, a postdoctoral researcher in Ding’s lab, analyzed the proteins associated with the inherited genomes of 1,064 individuals with 10 cancer types. The researchers identified 119 rare, cancer-causing genetic variants and additional common variants in cancer genes that may affect the structure, abundance and stability of key proteins involved with these cancer types. They also identified new, rare mutations strongly associated with cancer as well as common variants that, in concert, may tip the scales toward disease.