李佛美尼症候群 （Li-Fraumeni syndrome） 是一種罕見的遺傳性疾病。此症候群的家族有早發性癌症、同一個人得到多種不同的原發性癌症以及家族中有不同類型癌症的特徵。在許多LFS家族中都有發現生殖系TP53的突變。TP53為一腫瘤抑制基因 (tumor suppressor gene)，他在p53通道 (p53 pathway) 裡扮演一個很重要的角色。MDM2為TP53重要的負調節者 (negative regulator)，先前的研究指出在MDM2中的一個單核苷酸多型性 (SNP309, T→G 變異) 和弱化p53路徑以及加速腫瘤形成有關。有些研究指出在LFS家族中，性別會影響到罹癌風險。我們的目的為評估LFS家族中可能的癌症風險因子，包含生殖系TP53、MDM2 SNP309、性別以及其交互作用的聯合效應。
本研究之研究族群為19個李佛美尼症候群擴展家族，來自美國德州安德森癌症醫學中心　(The University of Texas MD Anderson Cancer Center (Houston, Texas))，其中包含19個指標個案及444名親屬。此世代被追蹤超過20年直至2001年12月31日。19個指標個案均為生殖系TP53突變攜帶者。在19個指標個案中，有6個罹患軟組織肉瘤、5個罹患骨肉瘤、8個滿足典型李佛美尼症候群的條件。有105名MDM2 SNP309 G等位基因攜帶者、89名基因型為T/T型，269名為未知的基因型。由於本研究族群為家族資料，因此必須考慮家族成員間的相關性。先前有研究使用Cox比例風險模式為模式基礎的遺傳分析軟體 (GAP)對此家族做癌症風險的分析，在本研究中，我們使用邏輯式迴歸為基礎的遺傳流行病學軟體 (SAGE) 6.4版的SEGREG程式進行分析。在SAGE中會計算每個模型的最大概似值的對數值 (the logarithm ln(L) of the maximum likelihood)，然後我們再進行概似比檢定 (likelihood ratio test) 檢定可能的癌症風險因子的顯著性。
在本研究族群中，男性指標個案平均得病年齡為12.7歲，女性指標個案平均得病年齡為14.5歲，扣除指標個案其他親屬平均得病年齡為35.48歲。我們先在不加入共變數 (covariate) 的情況下進行遺傳模型的分析，我們以顯性模型作為我們後續分析的遺傳模型，除了將顯性模型作為後續分析的遺傳模型，我們也分析了以加成性模型為基礎的遺傳模型。不加入共變數的模型參數的估計值被用來作為加入共變數模型的初始值。我們將潛在的癌症風險因子包含TP53、MDM2 SNP309、性別以及他們的交互作用作為共變數漸次加入模型中。我們比較不同模型來檢定個別風險因子的顯著性。我們首先評估個別風險因子的作用，然後再依序評估其交互作用。在以二元性狀作為反應變數的部分，我們發現在顯性模型中，TP53和MDM2 SNP309和罹癌風險有顯著相關。當加入罹病年齡進入模型，TP53和MDM2 SNP309仍然和罹病年齡有顯著相關。我們的結果顯示在LFS家族中，除了TP53以外，MDM2 SNP309的G等位基因和癌症風險是有相關的。在本研究中，TP53與癌症風險有很強的關聯，但MDM2 SNP309對於癌症風險的影響則較為和緩，與先前文獻相符 (Wu et al. 2011)。但在TP53與性別的交互作用的部分，和先前的研究相比 (Wu et al. 2006; Wu et al. 2011)，我們的研究並未發現在生殖系TP53突變攜帶者中，女性相較於男性得病年齡有提早的情況。
我們評估了LFS家族中可能的癌症風險因子，並估計其作用大小。並發現TP53與MDM2 SNP309為顯著影響家族癌症風險的因子，但與過去文獻不同的是我們並未觀察到TP53與性別的交互作用對此家族中帶有生殖系TP53突變者的影響。

Li-Fraumeni syndrome (LFS) is a rare inherited disorder. There are several features about LFS families: multiple primary tumors, various cancer sites and early cancer onset. Most LFS family members were germline TP53 mutation carriers. Previous studies had indicated that a single nucleotide polymorphism (SNP309, T→G variation) in MDM2 might attenuated the p53 pathway and influenced tumor formation. The purpose of our study is to estimate the joint effects of possible cancer risk factors including germline TP53 mutation, MDM2 SNP309, sex and their interactions in 19 LFS extended families. We used SEGREG program in in the Statistical Analysis for Genetic Epidemiology (SAGE) to analyze data in this study. We considered the binary trait and binary trait with age-of-onset variable as outcome variables. We used the dominant model and additive model as our underlying genetic model. We incorporated potential risk factors and their interactions as covariates into the models subsequently, including TP53, MDM2 SNP309 and sex. We compared different models to test the significance of risk factors. Our results indicated that TP53 and MDM2 SNP309 were significantly associated with cancer risk.

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