Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment.
Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment.
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DOI：
10.1200/edbk_201391
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发表时间：
2018-05-23
期刊：
影响因子：
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通讯作者：
Dolan, M Eileen
中科院分区：
文献类型：
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作者：
Morton, Lindsay M;Kerns, Sarah L;Dolan, M Eileen
不断增长的癌症幸存者往往面临治疗的不利影响，这对发病率和死亡率产生了重大影响。虽然某些不良反应被认为具有显著的遗传成分，但仍有许多工作要做，以了解生殖系遗传因素在治疗相关毒性发展中的作用。在这篇文章中，我们回顾了目前对癌症幸存者中一系列不良后果的遗传易感性的理解（例如，纤维化、泌尿和直肠毒性、耳毒性、化疗诱导的周围神经病变、随后的恶性肿瘤）。大多数以前的研究都集中在狭窄的范围内，研究候选基因和途径的变化，如药物代谢，DNA损伤和修复以及炎症。这些早期候选基因研究的结果很少在独立人群中得到重复。对基因组理解的进步、技术的改进和实验室成本的降低导致了最近的全基因组研究，这些研究不可知地询问整个基因组中的常见和/或罕见变异。具有同质治疗暴露的较大患者队列和明确结局的系统性确定以及在独立研究人群中的重复是研究设计的重要方面，并且越来越多地导致发现与本综述中考虑的每种不良结局相关的变异。从长远来看，经过验证的生殖系遗传相关性为更准确地识别出现不良治疗作用的最高风险患者带来了巨大的希望，这对一线治疗决策，长期随访指南的个性化以及潜在的毒性预防或治疗目标的识别具有重要意义。
The growing population of cancer survivors often faces adverse effects of treatment, which have a substantial impact on morbidity and mortality. Although certain adverse effects are thought to have a significant heritable component, much work remains to be done to understand the role of germline genetic factors in the development of treatment-related toxicities. In this article, we review current understanding of genetic susceptibility to a range of adverse outcomes among cancer survivors (e.g., fibrosis, urinary and rectal toxicities, ototoxicity, chemotherapy-induced peripheral neuropathy, subsequent malignancies). Most previous research has been narrowly focused, investigating variation in candidate genes and pathways such as drug metabolism, DNA damage and repair, and inflammation. Few of the findings from these earlier candidate gene studies have been replicated in independent populations. Advances in understanding of the genome, improvements in technology, and reduction in laboratory costs have led to recent genome-wide studies, which agnostically interrogate common and/or rare variants across the entire genome. Larger cohorts of patients with homogeneous treatment exposures and systematic ascertainment of well-defined outcomes as well as replication in independent study populations are essential aspects of the study design and are increasingly leading to the discovery of variants associated with each of the adverse outcomes considered in this review. In the long-term, validated germline genetic associations hold tremendous promise for more precisely identifying patients at highest risk for developing adverse treatment effects, with implications for frontline therapy decision-making, personalization of long-term follow-up guidelines, and potential identification of targets for prevention or treatment of the toxicity.