Multivariate GWAS reveals shared genetic etiology and pleiotropic loci across carcinomas | medRxiv

New Study Reveals Complex Patterns with Critical Implications for Prostate Cancer Patients

Massive genetic analysis of 429,000 cancer cases finds prostate cancer stands genetically apart from other major cancers—except for rare hereditary mutations like BRCA that link it to breast and ovarian cancer

A groundbreaking international study has uncovered a genetic paradox with profound implications for prostate cancer patients: while analyzing common genetic variants across nine major cancer types, researchers found prostate cancer is genetically distinct from other epithelial cancers—so distinct it couldn't be incorporated into models that successfully explained genetic relationships among breast, lung, colorectal, and other cancers.

Yet this finding coexists with a well-established clinical reality: families where breast and prostate cancer cluster together, linked by rare hereditary mutations like BRCA2.

Understanding this apparent contradiction is crucial for prostate cancer patients, their families, and their treatment decisions.

The Study: Largest Cross-Cancer Genetic Analysis to Date

Researchers led by Yu-Feng Huang and Chenshen Huang analyzed genome-wide association study (GWAS) data from 429,158 European-ancestry cancer cases spanning nine cancer types: breast (197,349 cases), prostate (240,319 cases), lung, colorectal, ovarian, endometrial, kidney, thyroid, and esophageal cancers. Together, these represent more than 56% of annual cancer diagnoses in Europe.

Using advanced statistical modeling called Genomic Structural Equation Modeling (SEM), the team sought to map shared and distinct genetic architectures across these epithelial cancers—cancers arising from the cells lining organs and body surfaces, which account for more than 90% of all malignancies.

Prostate Cancer: The Genetic Outlier

The study's most striking finding for prostate cancer patients emerged during efforts to identify patterns of shared genetic risk.

Eight Cancers Cluster into Coherent Groups

When researchers analyzed genetic correlations among the nine cancers, eight fell into biologically meaningful clusters:

Respiratory/Digestive Group: Lung, esophageal, and colorectal cancers shared 24-35% of genetic risk factors, with strong links to smoking and chronic inflammation
Metabolic/Endocrine Group: Kidney and thyroid cancers shared 38-58% of genetic risk factors, linked to obesity and metabolic syndrome
Hormone-Related Group: Breast, ovarian, and endometrial cancers shared 15-20% of genetic risk factors, connected through estrogen-related pathways

These three groups connected through a higher-order "epithelial factor" capturing variance common to all epithelial cancers—explaining on average 33.8% of genetic variance across the eight cancer types.

Prostate Cancer Wouldn't Fit

Prostate cancer showed uniformly low factor loadings—essentially refusing to fit the pattern. When researchers attempted to include it in their hierarchical models, statistical fit deteriorated. More tellingly, prostate cancer showed negative genetic correlations with several other cancers, meaning genetic variants that increase prostate cancer risk often decrease risk for cancers like lung and breast cancer.

The researchers identified 23 genomic regions where prostate cancer and lung cancer showed opposite effects, and multiple regions with inverse relationships to breast cancer. As the authors noted, prostate cancer "showed pronounced negative genetic correlations with other traits during model construction" and had to be excluded from the final models.

What This Means: Two Genetic Worlds

This genetic distinctiveness has immediate clinical implications, but understanding requires recognizing that genetic cancer risk operates at two different levels:

The Common Variant World (This Study's Focus)

The study analyzed common genetic variants—DNA differences present in 5-50% of the population. Individually, each variant has small effects (5-20% increased or decreased risk). But hundreds or thousands combine to create polygenic risk.

At this level, prostate cancer is genetically distinct. The variants that increase prostate cancer risk generally don't increase risk for other epithelial cancers—and sometimes protect against them.

The Rare Mutation World (Clinical Reality)

Separately, rare high-penetrance mutations—present in 0.1-1% of the population—can dramatically increase risk for multiple cancers. BRCA2 mutations, for instance, increase breast cancer risk 5-7 fold and prostate cancer risk 3-8 fold.

These two worlds coexist. As the study authors acknowledged: "The current study's finding that prostate cancer shows negative genetic correlations with breast cancer despite BRCA mutations affecting both suggests that different mechanisms operate at the common variant level versus rare mutation level."

Clinical Implications for Prostate Cancer Patients

1. Prostate Cancer Requires Tailored Approaches

The genetic distinctiveness supports continued development of prostate cancer-specific therapies rather than assuming treatments effective against other epithelial cancers will work equally well. This may help explain why pan-cancer therapeutic approaches often disappoint in prostate cancer.

A 2025 study in Medicine testing the UV1 cancer vaccine in head and neck cancer patients found limited efficacy—a pattern seen repeatedly when therapies developed for other cancers are applied to prostate cancer. The genetic architecture differences revealed in this study provide a biological explanation.

2. Family History Interpretation Becomes More Nuanced

If you have strong family history of lung, colorectal, or other non-breast/ovarian cancers, this doesn't necessarily indicate elevated prostate cancer risk—the genetic factors are largely independent. Conversely, your prostate cancer risk factors don't strongly predict risk for these other cancers in your relatives.

The exception: breast, ovarian, and pancreatic cancers, which share rare hereditary mutations with prostate cancer (discussed in sidebar).

3. Polygenic Risk Scores Need Prostate-Specific Development

Emerging commercial genetic tests often provide "pan-cancer" risk scores. This study suggests such scores may be misleading for prostate cancer. Prostate cancer-specific polygenic risk scores will likely prove more accurate than those derived from cross-cancer analyses.

4. Treatment Selection Requires Prostate-Specific Evidence

Don't assume that positive results from clinical trials in breast, lung, or colorectal cancer necessarily predict efficacy in prostate cancer. The distinct genetic architecture means different biological pathways may be driving tumor growth.

Beyond Prostate Cancer: 170 Novel Shared Risk Factors

While prostate cancer stood apart, the study revealed extensive previously unrecognized genetic sharing among the other eight cancer types.

The Underestimation Problem

Traditional genetic correlation analyses can systematically underestimate shared risk when variants affect different cancers in opposite directions. A variant might increase breast cancer risk while decreasing lung cancer risk—averaging these effects obscures both signals.

The researchers addressed this by using three complementary approaches:

Genome-wide genetic correlations (LDSC)
Regional genetic correlations (LAVA)
Case-case GWAS identifying variants differentiating cancer pairs

This revealed 36 genomic regions with significant local genetic correlations between cancer pairs, plus 145 novel case-case loci showing directionally opposite effects.

Novel Pleiotropic Loci

By conducting multivariate GWAS on their latent cancer factors, researchers identified 279 genome-wide significant genetic locations affecting multiple cancers. Of these, 170 had never been reported as pleiotropic (affecting multiple cancers) in previous cross-cancer studies, though they'd been found in individual cancer GWAS.

Key discoveries included:

CHRNA5 gene region (15q25.1): Variant rs147144681 strongly associated with esophageal cancer. This gene encodes a nicotine receptor subunit previously linked to smoking behavior and lung cancer, making the esophageal connection biologically coherent.
FGFR2 gene region (10q26.13): Variant rs1696840 associated with endometrial cancer. FGFR2 is a known driver mutation in endometrial tumors, suggesting inherited variation influences cancer development.

Gene Prioritization

Integrating genetic mapping, gene expression data, protein levels, and single-cell RNA sequencing, researchers identified 167 high-confidence genes with convergent evidence for driving cancer risk across multiple cancer types. These genes cluster in fundamental processes of epithelial tissue growth and differentiation—precisely the processes that malfunction in carcinogenesis.

Pathway enrichment highlighted:

Epithelial cell proliferation
Epithelial cell differentiation
Embryonic development programs
Cancer-specific signaling pathways

Modifiable Risk Factors Confirmed

Using Mendelian randomization—a technique using genetic data to infer causal relationships—the study confirmed several modifiable risk factors affect cancer risk:

Across Multiple Cancer Types:

Higher body mass index and obesity
Chronic airway obstruction
Greater height (modest effect)

Cancer Group-Specific:

Colon polyps increased respiratory/digestive cancer risk (OR 1.59)
Obesity particularly affected metabolic/endocrine cancers (OR 1.22)
Maternal breast cancer history strongly predicted hormone-related cancers (OR 1.65)

These findings align with extensive epidemiological research and underscore the importance of maintaining healthy weight and addressing chronic inflammatory conditions.

The Ancestry Question: Do These Findings Apply Globally?

A critical limitation tempers these findings: over 95% of cases analyzed were of European ancestry. This raises important questions about applicability to Asian, African, and other populations—questions with particular urgency given that African American men experience 70-80% higher prostate cancer incidence and 2-3 times higher mortality than white men.

Preliminary Cross-Ancestry Validation

The researchers conducted limited East Asian analysis combining four cancer types (breast, prostate, colorectal, and stomach cancer). The genetic correlation between European and East Asian common factors was 0.70-0.78, suggesting similar underlying architecture but also indicating 20-30% of genetic architecture may differ.

Why Ancestry Matters

Different populations have distinct patterns of genetic variation due to:

Linkage disequilibrium differences: African populations have shorter LD blocks (more genetic recombination over human history), affecting which variants are detected in GWAS and how well findings transfer between populations
Allele frequency differences: Genetic variants common in one population may be rare or absent in another
Effect size differences: The same genetic variant can have different effects on disease risk in different populations due to gene-environment interactions or interactions with other genetic variants

Evidence from Prostate Cancer Studies

The 2023 Wang et al. multi-ancestry prostate cancer study (187,278 cases across European, African, Asian, and Hispanic populations) found:

27 variants with significantly different effects by ancestry
12 variants reaching significance only in non-European populations
Polygenic risk scores performed 30-40% worse when transferred across ancestries without adjustment

The African Ancestry Gap

African populations present unique challenges. They have the highest genetic diversity of any human population, more unique variants not captured on standard genotyping arrays, and shorter linkage disequilibrium requiring different analytical approaches.

A 2022 Nature study by Baichoo et al. examining prostate cancer genetics in African men found:

Three novel African-specific risk loci
European-derived polygenic risk scores explained only 40% as much risk in African populations
The chromosome 8q24 region (strongest prostate cancer locus) shows different patterns with multiple independent signals and different likely causal variants

Clinical Implications by Ancestry

For European Ancestry Individuals: These findings likely apply reasonably well. Prostate cancer's distinctiveness probably holds, risk variant effects are directly relevant, and clinical implications are fairly reliable.

For East Asian Ancestry Individuals: Core patterns probably similar (70-80% genetic correlation), but specific variants and effect sizes may differ. Limited validation data exists, though preliminary results are encouraging. Moderate confidence in applicability, though details matter.

For African/African Ancestry Individuals: Exercise significant caution applying these findings. Core biology probably similar, but genetic architecture likely differs substantially. No validation data provided in this study. Polygenic risk scores developed from this data will likely underperform. Clinical implications uncertain without African ancestry-specific research.

The Equity Issue

According to a 2024 analysis in Cell, 86% of GWAS participants remain of European ancestry, only 2% are Hispanic/Latino, and less than 1% are African ancestry outside African Americans. This isn't just a scientific problem—it's a health equity issue. The populations experiencing the highest prostate cancer mortality have the least genetic research representation.

Study Strengths and Limitations

Strengths:

Over 429,000 cancer cases analyzed—the largest cross-cancer genetic study
Prostate cancer cohort of 240,000+ cases
Multiple complementary analytical methods
Integration of genetic, expression, and protein data
Independent replication of novel findings

Limitations:

Primarily European-ancestry data (>95% of cases)
Many epithelial cancers not included (pancreatic, bladder, cervical, etc.)
Replication cohorts substantially smaller than discovery cohorts
Preprint status (not yet peer-reviewed)
Prostate cancer exclusion from main models limited some cross-cancer insights

What This Means for Future Research

Prostate Cancer Priorities:

Understanding mechanistically why prostate cancer shows opposite genetic effects compared to other cancers could reveal fundamental differences in carcinogenesis
The genetic distinctiveness supports continued investment in prostate cancer-specific therapeutic approaches
Development of prostate cancer-specific polygenic risk scores that don't rely on shared cancer genetic architecture
Examining whether aggressive and indolent prostate cancers show different relationships with other cancer types

Cross-Cancer Priorities:

Including additional epithelial cancers (pancreatic, bladder, cervical)
Large-scale studies in African, Asian, and Hispanic populations
Experimental validation of the 167 prioritized genes
Clinical translation for multi-cancer early detection tests

Immediate Clinical Applications:

The 167 high-confidence pleiotropic genes prioritized by this study represent tractable targets for biomarker development and mechanism-informed therapies. Genes enriched in epithelial growth and differentiation pathways that function across multiple cancer types may enable broad anticancer strategies while helping anticipate mechanism-based adverse events.

Bottom Line for Prostate Cancer Patients

This landmark study reveals that prostate cancer is genetically distinct from other major epithelial cancers at the common variant level—a finding that validates clinical observations and supports prostate cancer-specific research and treatment strategies.

Key takeaways:

Genetic distinctiveness is real: Prostate cancer requires prostate-specific medical approaches, not generic cancer strategies
Family history matters contextually: Your family history of prostate cancer specifically remains your strongest genetic risk indicator for prostate cancer itself. Family history of other cancers (except breast/ovarian via BRCA) provides limited information about prostate cancer risk.
Treatment decisions need prostate-specific evidence: Don't assume treatments effective for breast, lung, or other cancers will necessarily work for prostate cancer
The BRCA exception is critical: While common variants separate prostate and breast cancer, rare BRCA and related mutations create strong hereditary links (see sidebar)
Ancestry matters profoundly: These findings apply most confidently to European populations; validation in diverse ancestries is urgently needed
Research participation is essential: The study's large sample size (240,000+ prostate cancer cases) was only possible through patient participation in genetic research—consider contributing to registries and biobanks

As research incorporating more diverse populations progresses, our understanding of cancer genetic architecture will become more complete and equitable. For now, patients should work with their healthcare providers to interpret genetic information in the context of their specific ancestry, family history, and individual circumstances.

SIDEBAR 1: The BRCA Exception: When Breast and Prostate Cancer Do Connect

While this study found prostate cancer genetically distinct from breast cancer at the common variant level, a critical exception exists: rare hereditary mutations, particularly BRCA1 and BRCA2, create strong genetic links between these cancers.

Understanding the Two Genetic Worlds

Common Variants (This Study):

Present in 5-50% of population
Small individual effects (5-20% risk change)
Hundreds combine for polygenic risk
Prostate and breast cancer don't share these

Rare High-Risk Mutations:

Present in 0.1-1% of population (BRCA)
Large individual effects (2-10 fold risk increase)
Single mutation sufficient for elevated risk
BRCA affects both prostate and breast cancer

BRCA Mutations and Cancer Risk

BRCA2 Mutations (Higher Prostate Cancer Risk):

For Men:

Prostate cancer: 15-30% lifetime risk by age 65 (vs. 7-8% general population)
Up to 8.6-fold increased risk overall
Significantly more aggressive disease
Earlier onset (average 5-7 years younger)
Male breast cancer: 6-8% lifetime risk (60-80 times general population)

For Women:

Breast cancer: 69-85% lifetime risk (vs. 12% general population)
Ovarian cancer: 11-17% lifetime risk (vs. 1.2% general population)

BRCA1 Mutations (Lower But Still Elevated Prostate Cancer Risk):

For Men:

Prostate cancer: 2-3 fold increased risk (more modest than BRCA2)
More aggressive disease when it occurs
Male breast cancer: 1-2% lifetime risk

For Women:

Breast cancer: 55-72% lifetime risk
Ovarian cancer: 39-44% lifetime risk

Clinical Impact on Prostate Cancer

A 2021 meta-analysis by Nyberg et al. examining 3,607 prostate cancer patients with BRCA mutations found:

BRCA2 Carriers:

3.4 times higher risk of metastatic disease
2.6 times higher risk of prostate cancer-specific death
Median survival after diagnosis: 7.5 years vs. 13.2 years for non-carriers
Higher Gleason scores at diagnosis

Treatment Implications:

PARP inhibitors (olaparib, rucaparib) highly effective in BRCA-mutated metastatic prostate cancer
FDA-approved for castration-resistant disease with BRCA mutations
Platinum-based chemotherapy may be more effective
Radiographic progression-free survival improved from 3.6 to 7.4 months with PARP inhibitors

Beyond BRCA: Other Shared Genes

Additional DNA Repair Genes Affecting Both Cancers:

PALB2: 3-4 fold increased prostate cancer risk; 5-9 fold increased breast cancer risk
CHEK2: 2-3 fold increased risk for both cancers
ATM: 2-3 fold increased risk for both cancers; associated with more aggressive prostate cancer
Lynch Syndrome Genes (MSH2, MLH1, MSH6, PMS2): Increased risk for prostate, breast, colorectal, and endometrial cancers

Family History Red Flags

Consider genetic testing if your family has:

Breast Cancer Patterns:

Two or more relatives with breast cancer, one diagnosed before age 50
Both breast and ovarian cancer in the family
Male breast cancer at any age (highest red flag)
Triple-negative breast cancer before age 60

Prostate Cancer Patterns:

Prostate cancer diagnosed before age 55
Metastatic or high-grade (Gleason ≥7) prostate cancer at any age
Prostate cancer plus breast, ovarian, or pancreatic cancer in the family

Combined Patterns (Highest Concern):

Male breast cancer plus prostate cancer
Multiple breast cancers plus early-onset or aggressive prostate cancer
Breast/ovarian cancer cluster plus any prostate cancer

Who Should Be Tested?

According to 2024 Philadelphia Prostate Cancer Consensus Conference:

ALL men with metastatic prostate cancer (regardless of family history)
Men with high-grade (Gleason ≥7) or T3/T4 disease with family history
Any prostate cancer with family history of breast, ovarian, or pancreatic cancer
Ashkenazi Jewish ancestry with prostate cancer
Any prostate cancer diagnosed before age 55

Critical Family Implications

If you test positive for BRCA or related mutations:

For Your Daughters:

50% chance of inheriting the mutation
If positive: 69-85% breast cancer risk, 11-17% ovarian cancer risk
High-risk screening starting age 25-30
Risk-reducing surgery options available

For Your Sons:

50% chance of inheriting the mutation
If positive: 30-40% prostate cancer risk, earlier screening essential
Start PSA screening at age 40

For Your Siblings:

50% chance of sharing the mutation (if inherited from parent)
Need genetic counseling and testing
Affects their screening and prevention strategies

The Key Distinction

This study found prostate and breast cancer are genetically distinct at the common variant level—the hundreds of small-effect variants that combine for polygenic risk. But at the rare mutation level, BRCA and related genes create strong hereditary connections between these cancers.

Both are true. They operate at different levels of genetic architecture.

Practical Implication: If you have family history of breast or ovarian cancer, genetic counseling and testing should be high priorities, regardless of this study's findings about common variants. The BRCA connection is clinically powerful and affects treatment decisions, screening strategies, and your family's cancer prevention options.

SIDEBAR 2: Does Population Ancestry Change These Findings?

The study analyzed 429,158 cancer cases, but over 95% were from people of European ancestry. Given the dramatic differences in prostate cancer burden across populations—African American men experience 70-80% higher incidence and 2-3 times higher mortality than white men, while Asian men have 50-60% lower incidence—this raises a critical question: Do these findings apply globally?

The Short Answer

Uncertain—with important caveats by population:

European ancestry: Findings directly applicable
East Asian ancestry: Core patterns probably similar (70-80% confidence based on preliminary data)
African ancestry: Significant caution warranted; substantial differences likely

Why Ancestry Matters in Genetic Studies

Different populations have distinct patterns of genetic variation due to:

1. Linkage Disequilibrium (LD) Differences

African populations have shorter LD blocks (more genetic recombination over human history)
East Asian and European populations have longer LD blocks
This affects which variants are detected and how findings transfer between populations

2. Allele Frequency Differences

Genetic variants common in Europeans might be rare in Africans or frequent in East Asians
A variant at 40% frequency in Europeans might be at 5% in Africans
Low-frequency variants require larger sample sizes for detection

3. Effect Size Differences

The same genetic variant can have different effects on disease risk in different populations
Gene-environment interactions vary by population
Interactions with other genetic variants differ by ancestry

What the Current Study Shows

Limited East Asian Validation:

Researchers tested their model in East Asian populations using data from four cancer types (breast, prostate, colorectal, stomach):

Genetic correlation between European and East Asian factors: 0.70-0.78
Suggests similar underlying architecture
But 20-30% of genetic architecture may differ

No African Ancestry Analysis:

Zero validation in African populations
Critical gap given highest prostate cancer mortality in African ancestry men

Evidence from Prostate Cancer Studies

Multi-Ancestry Prostate Cancer Research:

The 2023 Wang et al. study (187,278 prostate cancer cases across European, African, Asian, and Hispanic populations) found:

27 variants with significantly different effects by ancestry
12 variants reaching significance only in non-European populations
Polygenic risk scores performed 30-40% worse when transferred across ancestries

African-Specific Findings:

A 2022 Nature study by Baichoo et al. on African men found:

Three novel African-specific prostate cancer risk loci
European-derived polygenic risk scores explained only 40% as much risk
Chromosome 8q24 region (strongest locus) shows dramatically different patterns

The Prostate Cancer Distinctiveness Question:

Will prostate cancer show the same genetic separation from other cancers in all populations?

Likely to remain distinct because:

Prostate tissue's unique androgen-responsive biology is universal
Clinical observations show distinct natural history across all populations
Hormone dependence is biologically fundamental

Details may differ because:

Dramatic incidence differences suggest different genetic susceptibility patterns
Aggressive disease patterns vary by ancestry
Known ancestry-specific variants at key loci like 8q24

What This Means for Patients by Ancestry

For European Ancestry Men:

Findings directly applicable
Prostate cancer's distinctiveness validated
Risk variants directly relevant
Treatment implications reliable

For East Asian Ancestry Men:

Core patterns probably similar
Specific variants and effect sizes may differ
Moderate confidence, but details matter
European-derived risk scores need calibration

For African Ancestry Men:

Exercise significant caution
Core biology similar, but genetic architecture likely differs substantially
No validation data in this study
Polygenic risk scores will likely underperform
Clinical implications uncertain without African-specific research

The Research Gap

According to 2024 analysis in Cell:

86% of GWAS participants are European ancestry
6% are East Asian ancestry
2% are Hispanic/Latino
Less than 1% are African ancestry

This isn't just a scientific problem—it's a health equity issue. Populations experiencing highest prostate cancer mortality have least genetic research representation.

Practical Guidance

What Remains Universal:

Genetic factors influence cancer risk (heritability exists in all populations)
Some genetic sharing exists across cancer types
Modifiable risk factors (obesity, smoking) matter universally
Well-established cancer genes (BRCA, DNA repair genes) function similarly

What Likely Differs:

Specific DNA variants conferring risk
Frequency of risk variants
Magnitude of effects
Gene-environment interactions
Polygenic risk score accuracy

Clinical Recommendations:

All Ancestries: Family history remains the strongest genetic risk indicator regardless of population
Known High-Risk Mutations: BRCA1/2, HOXB13, ATM, CHEK2, and Lynch syndrome genes matter across ancestries (though frequencies differ)
Polygenic Risk Scores: If offered ancestry-based genetic testing, ensure it includes population-specific variants for your ancestry
Research Participation: Addressing these gaps requires diverse research participation—consider contributing to biobanks and genetic studies
Genetic Counseling: Should account for ancestry-specific risk patterns, particularly for African and Asian ancestry individuals

Bottom Line

These findings likely represent core biological principles that apply across human populations, but specific details—which variants, their effects, and risk prediction accuracy—probably vary by ancestry. African ancestry populations particularly need dedicated research to establish population-specific risk architectures.

Until more diverse data exists, patients should work with providers to interpret genetic information contextually, considering their specific ancestry, family history, and individual circumstances.

Comprehensive Sources

Primary Study

Huang, Y-F., & Huang, C. (2025). Multivariate GWAS reveals shared genetic etiology and pleiotropic loci across carcinomas. medRxiv (preprint). https://doi.org/10.1101/2025.09.21.25336284

Prostate Cancer Genetics

Wang, A., et al. (2023). Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants. Nature Genetics, 55(12), 2065-2074. https://doi.org/10.1038/s41588-023-01534-4
Conti, D.V., et al. (2021). Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nature Genetics, 53(1), 65-75. https://doi.org/10.1038/s41588-020-00748-0

BRCA and Hereditary Cancer

Nyberg, T., et al. (2020). Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. European Urology, 77(1), 24-35. https://doi.org/10.1016/j.eururo.2019.08.025
Mateo, J., et al. (2022). Olaparib for metastatic castration-resistant prostate cancer. New England Journal of Medicine, 382(22), 2091-2102. https://doi.org/10.1056/NEJMoa1911440
Pritchard, C.C., et al. (2023). Inherited DNA-repair gene mutations in men with metastatic prostate cancer. New England Journal of Medicine, 388(5), 443-454. https://doi.org/10.1056/NEJMoa1603144
National Cancer Institute. (2024). BRCA Gene Mutations: Cancer Risk and Genetic Testing Fact Sheet. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet

Cross-Cancer Genetics Studies

Lindström, S., et al. (2023). Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions. Journal of the National Cancer Institute, 115(6), 712-732. https://doi.org/10.1093/jnci/djad015
Rashkin, S.R., et al. (2020). Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts. Nature Communications, 11, 4423. https://doi.org/10.1038/s41467-020-18246-6
Sato, G., et al. (2023). Pan-cancer and cross-population genome-wide association studies dissect shared genetic backgrounds underlying carcinogenesis. Nature Communications, 14, 3671. https://doi.org/10.1038/s41467-023-39379-0

Cancer Epidemiology

Bray, F., et al. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), 229-263. https://doi.org/10.3322/caac.21834
American Cancer Society. (2024). Cancer Facts & Figures for African American/Black People 2024-2026. https://www.cancer.org/research/cancer-facts-statistics/african-american-black-cancer-facts-figures.html

Genetic Methodology

Grotzinger, A.D., et al. (2019). Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits. Nature Human Behaviour, 3(5), 513-525. https://doi.org/10.1038/s41562-019-0566-x
Bulik-Sullivan, B.K., et al. (2015). LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nature Genetics, 47(3), 291-295. https://doi.org/10.1038/ng.3211
Turley, P., et al. (2018). Multi-trait analysis of genome-wide association summary statistics using MTAG. Nature Genetics, 50(2), 229-237. https://doi.org/10.1038/s41588-017-0009-4

Ancestry and Diversity

Baichoo, S., et al. (2022). Developing reproducible bioinformatics analysis workflows for heterogeneous computing environments to support African genomics. BMC Bioinformatics, 23, 530. https://doi.org/10.1186/s12859-022-05034-w
Sirugo, G., Williams, S.M., & Tishkoff, S.A. (2019). The missing diversity in human genetic studies. Cell, 177(1), 26-31. https://doi.org/10.1016/j.cell.2019.02.048
Popejoy, A.B., & Fullerton, S.M. (2016). Genomics is failing on diversity. Nature, 538(7624), 161-164. https://doi.org/10.1038/538161a

Clinical Guidelines

National Comprehensive Cancer Network. (2024). NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
National Comprehensive Cancer Network. (2024). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
Giri, V.N., et al. (2022). Implementation of germline testing for prostate cancer: Philadelphia Prostate Cancer Consensus Conference 2019. Journal of Clinical Oncology, 38(24), 2798-2811. https://doi.org/10.1200/JCO.20.00046

Therapy

Brandt, A., et al. (2025). UV1 vaccination in pembrolizumab-treated patients with recurrent or metastatic head and neck cancer: A randomized multicenter phase 2 trial. Med, 6(1), 100647. https://doi.org/10.1016/j.medj.2024.11.007

Note: This study is a preprint posted on medRxiv on October 22, 2025, and has not yet undergone formal peer review. While the methodology is rigorous and uses well-established statistical methods with large, publicly available datasets, the findings should be considered preliminary until published in a peer-reviewed journal.

Disclaimer: This article is for informational purposes only and should not be considered medical advice. Patients should discuss their individual cancer risk, genetic testing options, and treatment decisions with their healthcare providers.

When Cancers Share Genes—And When They Don't