Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
BMC Med. 2024 Mar 14;22(1):120. doi: 10.1186/s12916-024-03305-2.
Numerous observational studies have highlighted associations of genetic predisposition of head and neck squamous cell carcinoma (HNSCC) with diverse risk factors, but these findings are constrained by design limitations of observational studies. In this study, we utilized a phenome-wide association study (PheWAS) approach, incorporating a polygenic risk score (PRS) derived from a wide array of genomic variants, to systematically investigate phenotypes associated with genetic predisposition to HNSCC. Furthermore, we validated our findings across heterogeneous cohorts, enhancing the robustness and generalizability of our results.
We derived PRSs for HNSCC and its subgroups, oropharyngeal cancer and oral cancer, using large-scale genome-wide association study summary statistics from the Genetic Associations and Mechanisms in Oncology Network. We conducted a comprehensive investigation, leveraging genotyping data and electronic health records from 308,492 individuals in the UK Biobank and 38,401 individuals in the Penn Medicine Biobank (PMBB), and subsequently performed PheWAS to elucidate the associations between PRS and a wide spectrum of phenotypes.
We revealed the HNSCC PRS showed significant association with phenotypes related to tobacco use disorder (OR, 1.06; 95% CI, 1.05-1.08; P = 3.50 × 10), alcoholism (OR, 1.06; 95% CI, 1.04-1.09; P = 6.14 × 10), alcohol-related disorders (OR, 1.08; 95% CI, 1.05-1.11; P = 1.09 × 10), emphysema (OR, 1.11; 95% CI, 1.06-1.16; P = 5.48 × 10), chronic airway obstruction (OR, 1.05; 95% CI, 1.03-1.07; P = 2.64 × 10), and cancer of bronchus (OR, 1.08; 95% CI, 1.04-1.13; P = 4.68 × 10). These findings were replicated in the PMBB cohort, and sensitivity analyses, including the exclusion of HNSCC cases and the major histocompatibility complex locus, confirmed the robustness of these associations. Additionally, we identified significant associations between HNSCC PRS and lifestyle factors related to smoking and alcohol consumption.
The study demonstrated the potential of PRS-based PheWAS in revealing associations between genetic risk factors for HNSCC and various phenotypic traits. The findings emphasized the importance of considering genetic susceptibility in understanding HNSCC and highlighted shared genetic bases between HNSCC and other health conditions and lifestyles.
大量观察性研究强调了头颈部鳞状细胞癌（HNSCC）的遗传易感性与多种风险因素之间的关联，但这些发现受到观察性研究设计局限性的限制。在这项研究中，我们利用表型全基因组关联研究（PheWAS）方法，结合源自广泛基因组变异的多基因风险评分（PRS），系统地研究与 HNSCC 遗传易感性相关的表型。此外，我们在异质队列中验证了我们的发现，增强了我们结果的稳健性和普遍性。
我们使用来自肿瘤遗传学和机制网络（Genetic Associations and Mechanisms in Oncology Network）的大规模全基因组关联研究汇总统计数据，为 HNSCC 及其亚组（口咽癌和口腔癌）推导 PRS。我们进行了全面的调查，利用来自英国生物库（UK Biobank）的 308,492 个人和宾夕法尼亚大学医学生物库（PMBB）的 38,401 个人的基因分型数据和电子健康记录，并随后进行了 PheWAS，以阐明 PRS 与广泛表型之间的关联。
我们发现 HNSCC PRS 与与烟草使用障碍（OR，1.06；95%CI，1.05-1.08；P=3.50×10）、酗酒（OR，1.06；95%CI，1.04-1.09；P=6.14×10）、酒精相关障碍（OR，1.08；95%CI，1.05-1.11；P=1.09×10）、肺气肿（OR，1.11；95%CI，1.06-1.16；P=5.48×10）、慢性气道阻塞（OR，1.05；95%CI，1.03-1.07；P=2.64×10）和支气管癌（OR，1.08；95%CI，1.04-1.13；P=4.68×10）相关的表型存在显著关联。这些发现在 PMBB 队列中得到了复制，敏感性分析，包括排除 HNSCC 病例和主要组织相容性复合体位点，证实了这些关联的稳健性。此外，我们还发现 HNSCC PRS 与与吸烟和饮酒有关的生活方式因素之间存在显著关联。
该研究表明，PRS 为基础的 PheWAS 具有揭示 HNSCC 遗传风险因素与各种表型特征之间关联的潜力。这些发现强调了在理解 HNSCC 时考虑遗传易感性的重要性，并突出了 HNSCC 与其他健康状况和生活方式之间的共同遗传基础。
