The Science Behind Polygenic Risk Scores - Cancer Associated Thrombosis

The Science Behind Polygenic Risk Scores - Cancer Associated Thrombosis (CAT)

The Science Behind Polygenic Risk Scores blog series features summaries* of a few of the promising studies researchers have completed in the PRS field and will provide you with some of the arenas in which PRS can prove useful for better-stratifying patient risk for various diseases.

*Please note that the following blog posts include information pulled directly from the referenced articles and may sometimes include direct quotes. For more detailed study information, including additional methods, discussion of study limitations, and more, please refer to the cited article(s) directly. 

Disease of Focus: Cancer-Associated Thrombosis

Research Citation: “Cancer-Associated thrombosis by cancer sites and inherited factors in a prospective population-based cohort.” (2023). Shi, Z., Wei, J., Rifkin, A.S., Wang, C-H., Billings, L.K., Woo, J.S.H., Talamonti, M.S., Vogel, T.J., Moore, E., Brockstein, B.E., Khandekar, J.D., Dunnenberger, H.M., Hulick, P.J., Duggan, D., Zheng, S.L., Lee, C.J., Helfand, B.T., Tafur, A.J., Xu, J. Thrombosis Research, 2023; 229; 69-72. https://www.thrombosisresearch.com/article/S0049-3848(23)00194-9/fulltext

Background

Blood clots that form in veins, or venous thromboembolism (VTE), are common and can cause major health issues and even death. Multiple factors contribute to VTE risk, including acquired factors (such as cancer) and inherited factors. Regarding the latter, it has been known that mutations in certain single genes, such as F5 and F2, increase VTE risk. Recently, genome-wide association studies (GWAS) have revealed multiple common single nucleotide polymorphisms (SNPs) associated with increased VTE risk. Polygenic risk scores (PRS) based on the combined presence or absence of such SNPs “has been shown to be effective to stratify VTE risk in the general population.”

Individuals with cancer have significantly higher rates of VTE (between 1% and 25%), and these occurrences are termed cancer-associated thrombosis (CAT). Certain individuals who are determined, by established guidelines, to be at higher risk for CAT are recommended to receive anti-clotting therapies (thromboprophylaxis). This would include those individuals with the above-mentioned genetic risk factors of F5 and/or F2 gene mutations and also those individuals with certain, higher-risk cancer types. The authors discuss that refining and updating CAT risk factors based on recent GWAS findings can better stratify those at the highest risk for CAT so that they can be managed more appropriately. Additionally, the authors assert that more clearly defining those types of cancer that infer higher risk is important for best supporting those individuals. 

Study Objective:

To estimate CAT rate by monogenic (single-gene) and polygenic (multiple genetic variants with a cumulative effect) factors and by primary cancer sites in patients with cancer from a prospective population-based cohort.

Methods and Findings:

The study was a retrospective analysis of prospectively collected data for CAT among 70,406 cancer patients from the UK Biobank (a large population-based cohort). Those individuals who received a cancer diagnosis after the initial study recruitment were included (with cancer diagnoses obtained from self-report, inpatient diagnosis, and/or the UK cancer registry). 

Genotypes for the well-known, somewhat common Factor V Leiden F5 gene mutation c.1601G>A and F2 gene mutation G20210A were obtained from the UK Biobank Axiom SNP array. Additionally, VTE risk-associated SNP status was obtained from the same array. A published PRS was calculated based on 1,092,045 SNPs. 

“The CAT rate during the entire follow-up and the first 12 months was estimated for patients, overall, in two CAT risk groups of cancer sites classified by the NCCN (National Comprehensive Cancer Network) guidelines (‘high’ and ‘average’), and by each cancer site.” The rates of CAT in patients with various cancer types were compared with the CAT rate in all patients with cancer to determine the association of CAT with cancer type. Additionally, associations between CAT risk and the three genetic risk factors (F5 and F2 gene mutations and PRS) were tested. 

During an average 5.88 years of follow-up after a cancer diagnosis, the CAT rate was 4.35%, occurring mostly (54.49%) in the first year. The 12-month CAT rate was 2.37%. The 12-month CAT rate “differed considerably among cancer sites,” as illustrated in the chart below.

Of note, six cancer sites classified by the NCCN guidelines as “high-risk” for CAT had actual CAT rates lower than 5% (bladder, myeloproliferative, testical, lymphoma, kidney, and female genital organs). And conversely, five cancer sites classified by the NCCN guidelines as “average-risk” for CAT had actual CAT rates higher than 5% (gallbladder, thymus, esophageal, liver, and penile). The authors note that these differences may be partly explained by the much larger sample used in this study than sample sizes in previous studies.

Fig. 1.12-month cancer-associated thrombosis (CAT) rate by the National Comprehensive Cancer Network (NCCN) guideline risk groups and each cancer site among cancer patients in the UK Biobank. Dots and lines indicate CAT rate and 95% confidence interval, respectively. Red and blue dots are for cancer sites classified as ‘high’ and ‘average’ risk by NCCN guidelines, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Regarding single genes, 4.1% of the sample (N=2,607) were F5 gene mutation carriers, and 2% (N=1,288) were F2 mutation carriers. The 12-month CAT incidence rate was 4.06% in those individuals with mutations in one or both of these genes, which is 1.64 times higher than in individuals without mutations in either of these genes. As would be expected based on previous studies, the CAT rate in individuals with two F2 gene mutations (homozygous or compound heterozygous) or with two F5 gene mutations was considerably higher, at 3.94 times the CAT risk in individuals with no gene mutations.

The PRS for VTE risk was also significantly associated with the 12-month CAT risk among the study cohort, at 3.16x average risk. The 12-month CAT incidence rate in those individuals in the top decile of PRS was 4.06%, similar to that of individuals with F2 or F5 gene mutations. However, most individuals in that top decile (71%) did NOT carry mutations in the F2 or F5 genes. 

Fig. 2. Inherited risk for cancer-associated thrombosis (CAT) in the UK Biobank. a) 12-month CAT rate by the mutation status of F5 and/or F2 genes, b) 12-month CAT rate by decile of PGSVTE, and c) Venn- diagram of three inherited risk factors among cancer patients. In Figures A and B, dots and lines indicate the CAT rate and 95% confidence interval, respectively. In Figure C, the blue, yellow, and orange circle represents the number of cancer patients in the UK Biobank with high PGSVTE (top 10 percentile), carriers of F5 factor V Leiden mutation, and carriers of F2 G20210A mutation, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Discussion

The results of this study demonstrate evidence that PRS for CAT rate can identify more than twice as many individuals at higher inherited risk of CAT than standard, monogenic genetic testing identifies, and these PRS are independent of an individual’s carrier status of those single gene mutations (in F2 and F5). Additionally, the study provided evidence that “CAT rate varies considerably by cancer sites and differs from the classification of current clinical guidelines.” These are exciting findings that, especially if confirmed by additional studies, have potential clinical utility in refining CAT risk assessment among individuals with cancer. This can then provide for a more personalized prevention and treatment plan. 

To read the research in the April 2023 Thrombosis Research Journal publication, please visit: https://www.thrombosisresearch.com/article/S0049-3848(23)00194-9/fulltext 

Series Overview: Behind the Science

Welcome to Behind the Science, a blog series dedicated to providing a peek behind the curtain of the cutting-edge work happening both here at GenomicMD and also in the greater field of polygenic research. This series will supply our readers with valuable insights via curated research articles and press releases, as well as interviews with key players at our laboratory and beyond. Each post will provide an in-depth look at the roles, aspirations, and contributions that collectively drive the success of GenomicMD and polygenics research as a whole. In this series you'll find:

• Conversations with our experts: Interviews that give insights into the meticulous processes that underpin our genetic testing services.
• Unique Medical Perspectives: Interviews with doctors who utilize polygenic screening to improve patient care via precision medicine.
• Personal journeys: Firsthand stories from patients about how polygenic testing has influenced their health decisions, lifestyle choices, and overall well-being.
• Curated Research Articles and Press Releases: Keep up to date with articles and other news that shed light on the latest advancements in polygenic research

Join us as we explore the world of genetic testing and the inspiring individuals who are shaping the future of healthcare, one discovery at a time. Welcome to GenomicMD’s "Behind the Science" – where understanding meets innovation.