Background

Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa).

Objective

To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden.

Design, setting, and participants

A cross-sectional study of 2391 localized PrCa patients was carried out.

Outcome measurements and statistical analysis

Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males.

Results and limitations

AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort.

Conclusions

DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing.

Patient summary

In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.

中文翻译：

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DNA 修复基因遗传突变与局限性前列腺癌的关联

背景

鉴定 DNA 修复基因中的种系突变对前列腺癌 (PrCa) 患者的个性化治疗具有重要意义。

客观的

在多样化的学术生物库中确定与局部 PrCa 相关的 DNA 修复基因，并确定基因检测负担。

设计、设置和参与者

对 2391 名局限性 PrCa 患者进行了横断面研究。

结果测量和统计分析

在 1588 名局部 PrCa 患者和 3273 名无癌男性中确定了 17 个 DNA 修复基因的遗传祖先和突变率（不包括体细胞干扰）。在生物库 PrCa 病例和无癌生物库和 gnomAD 男性之间进行了基因确定的欧洲 (EUR) 和非洲 (AFR) 血统个体的负担测试。

结果和局限性

具有局部 PrCa 的 AFR 个体的 DNA 修复基因突变率低于 EUR 个体（1.4% 对 4.0%，p  = 0.02）。局部 PrCa 患者的突变率与生物样本库和 gnomAD 对照组相似（EUR：4.0% vs 2.8%，p  = 0.15 vs 3.1%，p  = 0.04；AFR：1.4% vs 1.8%，p  = 0.8 vs 2.1 %，p  = 0.5）。基于基因的罕见变异关联测试显示，与 EUR 血统的 gnomAD 对照相比，只有BRCA2突变显着丰富（1.0% 对 0.28%， p  = 0.03）。在参与者中，21% 和 11% 符合高风险和极高风险标准；其中，3.7% 和 6.2% 有种系基因突变，1.0% 和 2.5% 有分别为BRCA2突变。本研究的局限性包括对相对较小的单一机构队列的分析。

结论

DNA 修复基因种系突变率在局部 PrCa 患者的学术生物库队列中很低，尤其是在 AFR 遗传血统的个体中。仅在高风险、极高风险局部和淋巴结阳性 PrCa 患者中，具有已发表的与 PrCa 关联证据的基因突变率超过 2.5%。这些发现强调了局部 PrCa 患者风险分层的重要性，以确定适合进行种系基因检测的患者。

患者总结

对于大多数发生局限性前列腺癌的患者，种系基因检测不太可能揭示遗传性 DNA 修复突变，无论种族如何。高风险特征增加了种系 DNA 修复突变的可能性。