In a recent study published in Nature communications, Researchers from the United Kingdom (UK) investigated associations between 1,463 plasma proteins and 19 cancers using observational and genetic approaches in UK Biobank participants. They found 618 protein-cancer associations and 317 cancer biomarkers, which included 107 cases detected in the seven years before the cancer was diagnosed.
Record
Proteins are crucial in most biological processes, including cancer development, and some serve as known cancer risk factors or biomarkers. While previous studies have identified individual proteins associated with cancer, new multiple proteomic techniques allow the simultaneous evaluation of proteins at a high scale, especially those that remain unexplored in the context of cancer risk.
Prospective studies are challenged by confounding and bias, but genetic variants affecting protein levels offer complementary evidence. Genetic predictors, esp cis-pQTLs (abbreviation for cis protein quantitative trait loci), provide powerful insights into protein-carcinoma associations. Integrating observational and genetic approaches enhances the identification of proteins potentially associated with cancer development and progression.
This combined methodology helps to understand cancer biology, identify therapeutic targets and discover diagnostic biomarkers. Therefore, in the present study, the researchers used an integrated multi-omics strategy that merges prospective cohort and exome variation studies to reveal the proteins potentially involved in cancer etiology.
About the study
The present study used data from the UK Biobank, a prospective cohort comprising 44,645 adults (after exclusion) aged 39 to 73 years, with a median follow-up of 12 years. Participants underwent assessments including a questionnaire, anthropometric measurements, and blood sample collection. Plasma samples were analyzed using the Olink Proximity Extension Assay to quantify 1463 proteins. Cancer and death registry data were obtained through file linkage with national registries. Exome sequencing data were used to investigate genetic associations with protein levels.
Results and discussion
Observational analyzes showed 4921 cancer cases at a mean age of 66.9 years. Those who developed cancer were found to be older, have higher rates of addictions and a family history of cancer compared to the overall analysis sample. Women with cancer tended to have fewer children, menarche earlier, higher rates of postmenopausal status, use of hormone replacement therapy, and no use of oral contraceptives.
A total of 371 proteins showed significant associations with the risk of at least one cancer, resulting in 618 protein-cancer associations. A total of 304 of these associations were associated with proteins enriched in messenger ribonucleic acid (mRNA) expression in tissues or candidate cells of cancer origin. While many associations were observed for proteins associated with hematological cancers with high mRNA expression in B-cells or T-cells, associations were also found for proteins with high mRNA expression in various other tissues such as liver, kidney, brain, stomach, the lung. , colon, esophagus and endometrium.
Hematologic malignancies, including non-Hodgkin lymphoma (NHL), diffuse large B-cell non-Hodgkin lymphoma (DLBCL), leukemia, and multiple myeloma, accounted for more than half of the identified associations.
Notable associations included TNFRSF13B and SLAMF7 with multiple myeloma risk, PDCD1 and TNFRSF9 with NHL risk, and FCER2 and FCRL2 with leukemia risk. In addition, associations were found for liver cancer (e.g. IGFBP7 and IGFBP3), kidney cancer (e.g. HAVCR1 and ESM1), lung cancer (e.g. WFDC2 and CEACAM5), lung cancer esophagus (eg REG4 and ST6GAL1), colon cancer (eg AREG and GDF15), stomach cancer (eg ANXA10 and TFF1), breast cancer (eg STC2 and CRLF1), prostate cancer (eg, GP2, TSPAN1, and FLT3LG), endometrial cancer (eg, CHRDL2, KLK4, and WFIKKN1 ), and ovarian cancer (eg, DKK4 and WFDC2).
Lower correlations were found for cancers of the pancreas, thyroid, melanoma, or lips and mouth. Pathway analyzes suggested that the adaptive immune response may play a role in hematological cancers. Little heterogeneity was observed after stratifying associations by sex.
A total of 107 protein-cancer associations remained valid seven years after blood sampling, while genetic analyzes supported 29. In addition, four associations were supported by both long time to diagnosis (>7 years) and analyzes involving cis-pQTL and exome-wide protein genetic scores (exGS): NHL was associated with CD74 and TNFRSF1B, leukemia with ADAM8, and lung cancer with SFTPA2. The findings revealed 38 proteins associated with cancer risk that are also targeted by currently approved drugs, suggesting potential for therapeutic intervention to reduce cancer risk.
Although this is the largest cohort study investigating circulating proteins and cancer to date, the analysis was limited to baseline protein levels, possibly underestimating risks due to regression dilution bias. It also showed limited power for rare cancer sites and underrepresented populations, which warrants further research in different cohorts.
conclusion
In conclusion, the study found several relationships between blood proteins and cancer risk, with many detectable within seven years before a cancer diagnosis. Genetic analyzes supported their possible role in cancer development. In addition, the findings could identify proteins that may help detect early stages of cancer in at-risk individuals, offering promising biomarkers for early diagnosis and improved patient outcomes.
