PO.PS01.03 · 人群科学
非裔美国人与欧裔美国人前列腺癌患者基因组突变的祖源相关差异
Ancestry-related differences in genomic mutations between African American and European American prostate cancer patients
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摘要 Abstract
中文摘要
背景。在前列腺癌（PCa）肿瘤发生过程中，体细胞突变随年龄累积，影响包括FOXA1和SPOP在内的关键驱动基因。PCa的突变全景存在显著的祖源相关差异：CDK12突变在非裔美国人（AA）中的发生率是欧裔美国人（EA）的两倍，而TMPRSS2-ERG融合在EA中（约50%）比在AA中（约25%）更为常见。尽管存在这些差异，全面的全基因组突变比较仍然有限。本研究阐明不同祖源之间的全基因组突变差异，以识别祖源特异性分子特征，从而改善风险分层和个体化治疗。
方法。我们分析了来自三个队列共19例患者的全基因组DNA测序数据：来自欧洲核苷酸档案库（PRJNA412953）的非洲人（AF，n=5），以及来自TCGA的AA（n=11）和EA（n=3）。将比对到hg38的测序文件使用R代码和Strand NGS软件进行重新校准、重新比对和SNP检测。在去除统计学离群值后，我们比较了各突变负荷类别，包括替换、插入、缺失、复杂突变、合子性模式、转换/颠换突变、Ti/Tv比值以及dbSNP变异。统计分析对样本量≥5的组采用Mann-Whitney U检验，对较小的组采用10,000次迭代的置换检验。
结果。全基因组SNP分析揭示了AF、AA和EA之间的不同模式。AA与EA相比在大多数类别中显示出显著差异（p<0.05）：所有基本变异类型（替换：p=0.0149；插入：p=0.0181；缺失：p=0.0181）、合子性模式（纯合：p=0.0174；杂合：p=0.0236）、转换/颠换突变（两者均p=0.0149）、Ti/Tv比值（p=0.0174）以及已知dbSNP变异（p=0.0149）。复杂变异（p=0.1708）和新变异（p=0.2766）未显示显著差异。AF与AA相比在几乎所有类别中均显示显著差异（p<0.05）：替换（p=0.0176）、插入（p=0.005）、缺失（p=0.0169）、复杂变异（p=0.0169）、杂合变异（p=0.0211）、转换（p=0.0176）、颠换（p=0.0052）、Ti/Tv比值（p=0.0047），以及已知变异（p=0.0046）和新变异（p=0.0186），但纯合变异除外（p=0.7155）。这些发现表明，与非洲大陆的AF相比，AA已经形成了独特的遗传特征，这很可能源于混血和环境因素。
结论。本全基因组分析证明了PCa中存在显著的祖源特异性突变差异，由于混血和环境因素，AA表现出不同于AF和EA的独特特征。这些发现强调了多样化基因组数据库、个体化精准肿瘤学以及在更大队列中进行验证的必要性。
查看英文原文 English abstract
Background. Somatic mutations accumulate with age in prostate cancer (PCa) tumorigenesis, affecting key driver genes including FOXA1 and SPOP. Significant ancestry-related differences exist in PCa's mutational landscape: CDK12 mutations occur twice as frequently in African Americans (AA) versus European Americans (EA), while TMPRSS2-ERG fusion is more common in EA (~50%) than AA (~25%). Despite these differences, comprehensive genome-wide mutational comparisons remain limited. This study elucidates genome-wide mutational differences between ancestries to identify ancestry-specific molecular signatures for improved risk stratification and personalized treatment.
Methods. We analyzed whole-genome DNA sequencing from 19 patients across three cohorts: Africans (AF, n=5) from the European Nucleotide Archive (PRJNA412953), AA (n=11), and EA (n=3) from TCGA. Sequencing files aligned to hg38 were processed using R codes and Strand NGS software for recalibration, realignment, and SNP detection. After removing statistical outliers, we compared mutational burden categories including substitutions, insertions, deletions, complex mutations, zygosity patterns, transition/transversion mutations, Ti/Tv ratios, and dbSNP variants. Statistical analysis employed Mann-Whitney U test for groups ≥5 samples or 10,000-iteration permutation test for smaller groups.
Results. Whole-genome SNP analysis revealed distinct patterns across AF, AA, and EA. AA versus EA showed significant differences (p<0.05) in most categories: all basic variant types (substitutions: p=0.0149; insertions: p=0.0181; deletions: p=0.0181), zygosity patterns (homozygous: p=0.0174; heterozygous: p=0.0236), transition/transversion mutations (both p=0.0149), Ti/Tv ratios (p=0.0174), and known dbSNP variants (p=0.0149). Complex variants (p=0.1708) and novel variants (p=0.2766) showed no significant differences. AF versus AA revealed significant differences (p<0.05) in nearly all categories: substitutions (p=0.0176), insertions (p=0.005), deletions (p=0.0169), complex variants (p=0.0169), heterozygous variants (p=0.0211), transitions (p=0.0176), transversions (p=0.0052), Ti/Tv ratios (p=0.0047), and both known (p=0.0046) and novel (p=0.0186) variants, except homozygous variants (p=0.7155). These findings indicate AA have developed distinct genetic profiles compared to continental AF, likely from admixture and environmental factors.
Conclusion. This genome-wide analysis demonstrates significant ancestry-specific mutational differences in PCa, with AA exhibiting distinct profiles from both AF and EA due to admixture and environmental factors. These findings underscore the need for diverse genomic databases, personalized precision oncology, and validation in larger cohorts.
利益披露 Disclosure
N. S. Korvink, None..
A. Rezazadeh, None..
M. McClelland, None..
F. Rahmatpanah, None.