Numerous cancer genomic investigations have concentrated on alterations within the tumor itself and how these genetic variations enable a tumor to proliferate uncontrollably. A recent investigation, spearheaded by scholars at Washington University School of Medicine in St. Louis, delves deeply into heritable cancer mutations identified in a healthy blood sample and reveals how such mutations may impose repercussions on the body’s cells from birth, potentially making an individual more susceptible to developing cancers throughout different phases of life.
The researchers examined the inherited genomes of over 1,000 cancer patients to establish how inherited mutations — referred to as germline variants — lead to defective proteins, which consequently can disrupt physiological functions. The results bear significance for assessing an individual’s inherited cancer risk and guiding potential novel approaches for prevention, early identification, and treatment.
This study is set to be published on April 14 in the journal Cell.
“This is crucial foundational research for the field,” stated senior author Li Ding, the David English Smith Distinguished Professor of Medicine at WashU Medicine. “It is essential to understand how germline variants — whether rare or common — might affect the protein machinery that operates our bodies and what those effects could imply for cancer development throughout one’s lifetime.”
This study marks a significant milestone within the initiatives of the Clinical Proteomic Tumor Analysis Consortium, a nationwide collaboration supported by the National Cancer Institute of the National Institutes of Health (NIH) aimed at elucidating the roles of all cellular proteins involved in cancer initiation and progression. Every individual is born with germline variants — some of which are significant, some insignificant, and many uncertain — and throughout life, various tissues acquire their own mutations. Tumors typically possess a unique array of new mutations that have been the centerpiece of most clinical inquiries. In this new research, attention is shifted to inherited germline variants, in contrast to those acquired later on.
Healthcare providers can present individuals with certain inherited mutations — such as those found in two BRCA genes, known to elevate breast cancer risk — options for lowering their likelihood of developing cancer. These measures include more frequent breast cancer screenings, preventive chemotherapy, and surgical interventions. The current study amplifies the value of understanding cancer risks associated with germline mutations by scrutinizing the genomes of healthy cells from over 1,000 cancer patients.
The team, co-directed by first author Fernanda Martins Rodrigues, a postdoctoral researcher in Ding’s lab, investigated the proteins linked to the inherited genomes of 1,064 individuals across 10 cancer types. The researchers discovered 119 rare, cancer-inducing genetic variants as well as additional common variants in cancer-related genes that may influence the structure, quantity, and stability of crucial proteins associated with these types of cancer. They also found new, rare mutations strongly correlated with cancer, alongside common variants that, when acting collectively, may tilt the balance toward disease.
BRCA genes,” remarked Ding, who is also a research member of Siteman Cancer Center, affiliated with Barnes-Jewish Hospital and WashU Medicine. “This analysis now introduces more common variants that might not individually cause cancer but seem to work together to impact significant pathways involved in cancer.”
To assess the combined effect of the various variants identified that may influence cancer risk, the researchers computed what is known as a polygenic risk score for each patient. This score can estimate the overall cancer risk derived from all the mutations considered together. If an individual possesses only one or two inherited variants that predispose them to cancer, the effect may not be substantial. However, inheriting multiple such variants could lead to an elevated risk.
The researchers discovered that patients with the aggressive brain cancer glioblastoma, pancreatic cancer, or an aggressive form of lung cancer exhibited significantly higher polygenic risk scores compared to healthy individuals or even those who developed other cancer types. For patients with any type of cancer, those with elevated polygenic risk scores experienced more aggressive disease.
Based on their protein analysis, Ding and her colleagues found that several inherited risk variants, while apparently independent, influenced downstream effects that converged on specific biological processes, such as certain immune functions and protein stability.
One particularly revealing aspect of the study was the authors’ investigation into how inherited mutations could affect structural modifications that proteins may undergo post-assembly. Two of these crucial alterations entail the addition of small molecular tags to a protein at specific sites. These tags can significantly impact how a given protein functions, such as determining its activity levels and timing.
Relying solely on genome sequencing — without accurately matching germline mutations to their effects on proteins, as done by Ding and her co-authors — will overlook these critical modifications. This type of research enriches the understanding of the genetic factors that elevate cancer risk, which could, in turn, enhance the precision of polygenic risk scores down the line.
Rodrigues FM, Terekhanova NV, Imbach KJ, Clauser KR, Selvan ME, Mendizabal I, Geffen Y, Akiyama Y, Maynard M, Yaron TM, Li Y, Cao S, Storrs EP, Gonda OS, Gaite-Reguero A, Govindan A, Kawaler EA, Wyczalkowski MA, Klein RJ, Turhan B, Krug K, Mani DR, da Veiga Leprevost F, Nesvizhskii AI, Carr SA, Fenyo D, Gillette MA, Colaprico A, Iavarone A, Robles AI, Huang K, Kumar-Sinha C, Aguet F, Lazar AJ, Cantley LC, Marigorta UM, Gumus ZH, Bailey MH, Getz G, Porta-Pardo E, Ding L, Clinical Proteomic Tumor Analysis Consortium. Precision proteogenomics reveals pan-cancer impact of germline variants. Cell. April 14, 2025.
This effort was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) under grant numbers U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, U01CA214125, U24CA210972, U24CA210979, and U24CA270823; and contract GR0012005; the Spanish Ministry of Science, under grants RYC2019-026415-I, PID2019-107043RA-I00, RYC2019-026415-I, PID2019-107043RA-I00, RYC2020-030632-I, PID2019-108244RA-I00; and the Fundación Cris Contra el Cáncer (PR TPD 2020-19). Much of this research has utilized the UK Biobank Resource through Application Numbers 54343 and 74382. Data utilized in this publication were produced by the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC), accessible via dbGaP accession numbers phs000892.v6.p1 (“CPTAC Proteogenomic Confirmatory Study”) and phs001287.v17.p6 (“CPTAC Proteogenomic Study”). This initiative has been partially funded with federal resources from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I, Task Order No. HHSN26100064.
The content reflects solely the perspectives of the authors and does not necessarily represent the official viewpoints of the NIH.
About Washington University School of Medicine
WashU Medicine stands as a premier authority in academic medicine, encompassing biomedical research, patient care, and educational initiatives with a faculty of 2,900. Its National Institutes of Health (NIH) research funding portfolio ranks as the second largest among U.S. medical schools and has experienced a 56% increase over the past seven years. In conjunction with institutional investments, WashU Medicine dedicates well over $1 billion annually toward basic and clinical research innovation and education. Its faculty practice consistently ranks in the top five across the nation, consisting of over 1,900 faculty physicians working across 130 locations, who also serve as the medical staff for Barnes-Jewish and St. Louis Children’s hospitals within BJC HealthCare. WashU Medicine boasts a rich legacy in MD/PhD training, having recently allocated $100 million towards scholarships and curriculum enhancement for its medical students, and is home to exemplary training programs across every medical subspecialty along with physical therapy, occupational therapy, and audiology and communications sciences.
Initially published on the WashU Medicine website
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