Donald Neil, Malik Salim, McGuire Joshua L, Monahan Kevin J
Faculty of Medicine, Imperial College London, London, UK.
Family History of Bowel Cancer Clinic, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, UK.
Fam Cancer. 2018 Jan;17(1):43-52. doi: 10.1007/s10689-017-9995-8.
Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually. LS is characterised by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. The penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether low penetrance genetic risk factors may result in phenotype modification in LS patients. To conduct a systematic literature review and meta-analysis to assess the association between low penetrance genetic risk modifiers and CRC in LS patients. A systematic review was conducted of the PubMed and HuGENet databases. Eligibility of studies was determined by pre-defined criteria. Included studies were analysed via the per-allele model and assessed by pooled odds ratios and establishing 95% confidence intervals. Study heterogeneity was assessed via Cochrane's Q statistic and I2 values. Publication bias was evaluated with funnel plots. Subgroup analysis was conducted on gender. Statistical software used was the Metafor package for the R programme version 3.1.3. Sixty-four polymorphisms were identified and sufficient data was available for analysis of ten polymorphisms, with between 279 and 1768 CRC cases per polymorphism. None demonstrated association with CRC risk in LS patients. However in sub-group analysis the polymorphism rs16892766 (8q23.3) was significant in males (OR 1.53, 95% CI 1.12-2.10). The variable phenotype presentation of the disease still remains largely unexplained, and further investigation is warranted. Other factors may also be influencing the high variability of the disease, such as environmental factors, copy number variants and epigenetic alterations. Investigation into these areas is needed as well as larger and more definitive studies of the polymorphisms analysed in this study.
林奇综合征（LS）是一种具有高度遗传易感性的遗传性癌症综合征，在英国每年约有1000例结直肠癌（CRC）与之相关。LS的特征是常染色体显性遗传以及DNA错配修复基因中的种系突变。其遗传率差异很大，原因尚未完全阐明。本研究调查低遗传率遗传风险因素是否可能导致LS患者的表型改变。进行系统的文献综述和荟萃分析，以评估低遗传率遗传风险修饰因子与LS患者CRC之间的关联。对PubMed和HuGENet数据库进行了系统综述。根据预先定义的标准确定研究的纳入资格。纳入的研究通过等位基因模型进行分析，并通过合并比值比和建立95%置信区间进行评估。通过Cochrane's Q统计量和I2值评估研究异质性。用漏斗图评估发表偏倚。按性别进行亚组分析。使用的统计软件是R程序版本3.1.3的Metafor包。共鉴定出64个多态性，有足够数据可用于分析10个多态性，每个多态性的CRC病例数在279至1768例之间。没有一个显示与LS患者的CRC风险相关。然而，在亚组分析中，多态性rs16892766（8q23.3）在男性中具有显著性（比值比1.53，95%置信区间1.12 - 2.10）。该疾病可变的表型表现仍 largely unexplained，需要进一步研究。其他因素也可能影响该疾病的高度变异性，如环境因素、拷贝数变异和表观遗传改变。需要对这些领域进行研究，以及对本研究中分析的多态性进行更大规模、更明确的研究。
