Ndou Lutricia, Chambuso Ramadhani, Algar Ursula, Goldberg Paul, Boutall Adam, Ramesar Raj
UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, and Affiliated Hospitals, Cape Town 7704, South Africa.
The Colorectal Unit of the Department of Surgery, Groote Schuur Hospital, The University of Cape Town, Cape Town 7925, South Africa.
Biomedicines. 2024 Sep 27;12(10):2201. doi: 10.3390/biomedicines12102201.
High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the gene. A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in , , , , , , , , , , , , , , , , genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan-Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A -value < 0.05 after correcting for multiple testing using the Benjamini-Hochberg method was considered significant at a 95% confidence interval. We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The rs4646903 risk (GG) and rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01-4.08], = 0.034 and Adj HR: 1.53 [1.09-2.14], = 0.015, respectively). LSVH who were heterozygous for the rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48-0.99], = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06-2.09], corrected = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37-0.73], and Adj HR: 0.51 [CI: 0.36-0.74], both corrected < 0.001). Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the gene.
林奇综合征（LS）患者癌症诊断年龄的高度变异性已被广泛观察到，即使是在错配修复（MMR）基因中具有相同种系致病变异（PV）的亲属中也是如此。遗传多态性和生活方式因素被认为是导致这种变异性的原因。我们在一个具有南非创始种系PV c.1528C>T基因的同质LS队列中，研究了先前报道的遗传多态性对癌症诊断年龄的影响。使用多重聚合酶链反应和MassArray方法，对来自60个不同家庭的359名LS变异杂合子（LSVH）进行了基因分型，以检测 、 、 、 、 、 、 、 、 、 、 、 、 、 、 基因中的特定遗传多态性。采用Kaplan-Meier生存分析、单变量和多变量Cox比例风险伽马共享脆弱模型，并对性别进行校正，以估计癌症诊断年龄与多态性基因型之间的关联。使用Benjamini-Hochberg方法进行多重检验校正后，P值<0.05在95%置信区间被认为具有显著性。我们在细胞周期调控、DNA修复和外源性代谢基因中鉴定出三种基因型，它们与该队列中的癌症诊断年龄显著相关。rs4646903风险（GG）基因型和rs3734166多态性（GA+AA）基因型分别与癌症诊断年龄较小的风险增加显著相关（校正后风险比：2.03 [1.01 - 4.08]；P = 0.034和校正后风险比：1.53 [1.09 - 2.14]；P = 0.015）。rs1051685 SNP杂合的LSVH对癌症诊断年龄较小具有显著的保护作用（校正后风险比：0.69 [置信区间，0.48 - 0.99]；P = 0.043）。携带一到两种风险基因型的LS携带者在任何癌症诊断时年龄较小的风险显著较高（校正后风险比：1.49 [置信区间：1.06 - 2.09]；校正后P = 0.030），而携带一到两种保护基因型则显著降低了在年轻时患任何癌症和结直肠癌的风险（校正后风险比：0.52 [置信区间：0.37 - 0.73]，以及校正后风险比：0.51 [置信区间：0.36 - 0.74]，两者校正后P < 0.001）。细胞周期调控、DNA修复和外源性代谢基因中的多态性基因型可能会影响一个具有南非创始种系PV c.1528C>T基因的同质LS队列中的癌症诊断年龄。
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