Inherited Genes Play Key Role in Cancer Development

A major new study has revealed that inherited genetic abnormalities—known as germline variants—play a significant role in cancer progression. Conducted by an international team of scientists, including Kathleen J. Imbach and researchers from the Josep Carreras Leukaemia Research Institute (IJC), the study offers fresh insights into how these inherited mutations influence cellular behavior across various cancer types.

Back in 2022, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) explored the biology of cancer cells—already known to be highly altered—and showed how DNA mutations lead to changes in proteins that cause abnormal cell function. Now, in a continuation of that effort, the same group has found compelling evidence that many of these protein-altering mutations are inherited, passed down directly from a patient’s parents.

Published in the journal Cell, the new research examines the effects of germline variants on the cancer proteome—the full set of proteins expressed in cells.

With data from more than 1,000 patients across ten cancer types, this is among the most comprehensive studies to date on the connection between inherited genetic mutations and the cellular mechanisms that drive cancer. Kathleen J. Imbach and Dr. Eduard Porta, from IJC’s Cancer Immunogenomics group, are credited as co-first authors and co-senior supervisors on the paper.

Drawing on CPTAC’s extensive datasets—including genomic, transcriptomic, proteomic, acetylomic, and phosphoproteomic profiles—the team analyzed over 337,000 germline variants to assess their effects on protein expression and function.

Their analysis uncovered 119 germline variants—some rare, others common—in key cancer-related genes. These variants were shown to affect protein structure, abundance, and critical cellular functions such as protein stability, post-translational modification, and signaling.

Importantly, the findings underscore that germline variants don’t just increase cancer risk—they also influence the underlying biology of tumors. By integrating proteomic and genomic data, researchers were able to directly link inherited mutations to specific protein-level changes in individual patients. This mapping offers a clearer picture of how these genetic variants contribute to tumor development and progression.

One of the study’s most significant contributions lies in its use of a proteogenomic approach—termed “precision peptidomics” by the authors—which allowed the team to move beyond correlation and uncover the actual mechanisms through which seemingly benign inherited variants can collectively influence cancer risk.

The work opens new avenues for personalized cancer treatment and prevention by deepening our understanding of how inherited genetic traits affect protein function in cancer.

The research was supported by the National Cancer Institute (USA), the Spanish Ministry of Science, Innovation and Universities, and Fundación Cris contra el Cáncer (Spain).