Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis.
Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis.
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DOI：
10.1001/jamaoncol.2021.4398
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发表时间：
2021-12-01
期刊：
影响因子：
28.4
通讯作者：
Malkin D
中科院分区：
文献类型：
--
作者：
Kratz CP;Freycon C;Maxwell KN;Nichols KE;Schiffman JD;Evans DG;Achatz MI;Savage SA;Weitzel JN;Garber JE;Hainaut P;Malkin D
与TP53 （Li-Fraumeni综合征患者的基因变异）变异相关的表型谱是什么？表型差异背后的机制是什么？在这项队列研究中，我们定义了Li-Fraumeni谱系内的表型，并对来自1282个家庭的3034人的数据进行了分析和分类，这些数据来自国际癌症研究机构TP53数据库，以揭示符合和不符合Li-Fraumeni综合征检测标准的患者之间TP53变异分布的有意义的差异。研究结果表明，这种分类是了解导致Li-Fraumeni谱系表型差异的因素的潜在步骤，并可能作为其他癌症风险增加的遗传疾病重新分类的模型。Li-Fraumeni综合征是一种癌症易感性综合征，与致病性TP53种系变异引起的广谱癌症的高终生风险相关。缺乏一个反映自基因发现以来进化的广泛表型谱的定义，导致表型差异的机制在很大程度上仍然未知。定义Li-Fraumeni综合征的表型谱，并在整个表型谱中进行表型-基因型关联。我们分析并分类了国际癌症研究机构TP53数据库的种系变异数据集，该数据库包含自1990年以来科学文献中报道的来自1282个家族的3034人的数据。我们定义了术语Li-Fraumeni谱包括(1)表型的Li-Fraumeni综合征，定义为在符合临床Li-Fraumeni综合征标准的个人/家庭中缺乏致病性/可能致病性TP53变异；(2) Li-Fraumeni综合征，定义为在符合Li-Fraumeni综合征检测标准的个人/家庭中存在致病性/可能致病性TP53变异；(3)减弱型Li-Fraumeni综合征，定义为在不符合Li-Fraumeni综合征检测标准的癌症患者/家族中存在致病性/可能致病性TP53变异；(4)偶发性Li-Fraumeni综合征，定义为在没有癌症病史的个人/家族中存在致病性/可能致病性TP53变异。数据分析时间为2020年11月至2021年3月。种系TP53变异患者符合与不符合Li-Fraumeni综合征检测标准的变异分布和癌症特征的差异肿瘤谱差异有统计学意义，符合Li-Fraumeni综合征基因检测标准的患者（n = 2139）有更多早期肾上腺（n = 166, 6.5% vs n = 0）、脑（n = 360, 14.17% vs n = 57, 7.46%）、结缔组织（n = 303, 11.92% vs n = 56, 7.33%）和骨肿瘤（n = 279, 10.98% vs n = 3, 0.39%）。不符合Li-Fraumeni综合征基因检测标准的携带者（n = 678）有更多的乳腺癌（n = 292, 38.22% vs n = 700, 27.55%）和其他癌症，其中45%发生在45岁以后。两组均存在热点变异。一些变体仅在Li-Fraumeni综合征患者中发现，而其他变体仅在减毒Li-Fraumeni综合征患者中发现。在符合Li-Fraumeni综合征基因检测标准的患者中，大多数TP53变异被归类为致病性/可能致病性（2139例中有1757例，82.2%），而在不符合Li-Fraumeni综合征基因检测标准的患者中，40.4%（678例中有404例）的TP53变异被归类为意义不确定、结果相互矛盾、可能为良性、良性或未知的变异。这项队列研究的结果表明，这种新的分类，Li-Fraumeni谱，是朝着理解导致表型差异的因素迈出的一步，并可能作为其他癌症易感性综合征的模型。本队列研究检查了Li-Fraumeni综合征的表型谱，并在整个表型谱中进行了表型-基因型关联。
What is the phenotypic spectrum associated with variants in TP53, the gene variant in persons with Li-Fraumeni syndrome, and what mechanisms underlie phenotypic differences? In this cohort study, the phenotypes within the classification Li-Fraumeni spectrum were defined, and data from 3034 persons from 1282 families with data available in the International Agency for Research on Cancer TP53 Database were analyzed and classified to reveal meaningful differences in the TP53 variant distribution between patients who met vs those who did not meet Li-Fraumeni syndrome testing criteria. The study results suggest that this classification is a potential step toward understanding the factors that lead to phenotypic differences in the Li-Fraumeni spectrum and may serve as a model for the reclassification of other hereditary conditions with an increased cancer risk. Li-Fraumeni syndrome is a cancer predisposition syndrome that is associated with a high, lifelong risk of a broad spectrum of cancers that is caused by pathogenic TP53 germline variants. A definition that reflects the broad phenotypic spectrum that has evolved since the gene discovery is lacking, and mechanisms leading to phenotypic differences remain largely unknown. To define the phenotypic spectrum of Li-Fraumeni syndrome and conduct phenotype-genotype associations across the phenotypic spectrum. We analyzed and classified the germline variant data set of the International Agency for Research on Cancer TP53 database that contains data on a cohort of 3034 persons from 1282 families reported in the scientific literature since 1990. We defined the term Li-Fraumeni spectrum to encompass (1) phenotypic Li-Fraumeni syndrome, defined by the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2) Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3) attenuated Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer who does not meet Li-Fraumeni syndrome testing criteria; and (4) incidental Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer. Data analysis occurred from November 2020 to March 2021. Differences in variant distribution and cancer characteristics in patients with a germline TP53 variant who met vs did not meet Li-Fraumeni syndrome testing criteria. Tumor spectra showed significant differences, with more early adrenal (n = 166, 6.5% vs n = 0), brain (n = 360, 14.17% vs n = 57, 7.46%), connective tissue (n = 303, 11.92% vs n = 56, 7.33%), and bone tumors (n = 279, 10.98% vs n = 3, 0.39%) in patients who met Li-Fraumeni syndrome genetic testing criteria (n = 2139). Carriers who did not meet Li-Fraumeni syndrome genetic testing criteria (n = 678) had more breast (n = 292, 38.22% vs n = 700, 27.55%) and other cancers, 45% of them occurring after age 45 years. Hotspot variants were present in both groups. Several variants were exclusively found in patients with Li-Fraumeni syndrome, while others where exclusively found in patients with attenuated Li-Fraumeni syndrome. In patients who met Li-Fraumeni syndrome genetic testing criteria, most TP53 variants were classified as pathogenic/likely pathogenic (1757 of 2139, 82.2%), whereas 40.4% (404 of 678) of TP53 variants identified in patients who did not meet the Li-Fraumeni syndrome genetic testing criteria were classified as variants of uncertain significance, conflicting results, likely benign, benign, or unknown. The findings of this cohort study suggest that this new classification, Li-Fraumeni spectrum, is a step toward understanding the factors that lead to phenotypic differences and may serve as a model for other cancer predisposition syndromes. This cohort study examines the phenotypic spectrum of Li-Fraumeni syndrome and conducts phenotype-genotype associations across the phenotypic spectrum.
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影响因子：
30.8
作者：
Holmfeldt, Linda;Wei, Lei;Diaz-Flores, Ernesto;Walsh, Michael;Zhang, Jinghui;Ding, Li;Payne-Turner, Debbie;Churchman, Michelle;Andersson, Anna;Chen, Shann-Ching;McCastlain, Kelly;Becksfort, Jared;Ma, Jing;Wu, Gang;Patel, Samir N.;Heatley, Susan L.;Phillips, Letha A.;Song, Guangchun;Easton, John;Parker, Matthew;Chen, Xiang;Rusch, Michael;Boggs, Kristy;Vadodaria, Bhavin;Hedlund, Erin;Drenberg, Christina;Baker, Sharyn;Pei, Deqing;Cheng, Cheng;Huether, Robert;Lu, Charles;Fulton, Robert S.;Fulton, Lucinda L.;Tabib, Yashodhan;Dooling, David J.;Ochoa, Kerri;Minden, Mark;Lewis, Ian D.;To, L. Bik;Marlton, Paula;Roberts, Andrew W.;Raca, Gordana;Stock, Wendy;Neale, Geoffrey;Drexler, Hans G.;Dickins, Ross A.;Ellison, David W.;Shurtleff, Sheila A.;Pui, Ching-Hon;Ribeiro, Raul C.;Devidas, Meenakshi;Carroll, Andrew J.;Heerema, Nyla A.;Wood, Brent;Borowitz, Michael J.;Gastier-Foster, Julie M.;Raimondi, Susana C.;Mardis, Elaine R.;Wilson, Richard K.;Downing, James R.;Hunger, Stephen P.;Loh, Mignon L.;Mullighan, Charles G.
通讯作者：
Mullighan, Charles G.
影响因子：
39.2
作者：
LI, FP;FRAUMENI, JF
通讯作者：
FRAUMENI, JF
影响因子：
56.9
作者：
MALKIN, D;LI, FP;FRIEND, SH
通讯作者：
FRIEND, SH
影响因子：
120.7
作者：
LI, FP;FRAUMENI, JF
通讯作者：
FRAUMENI, JF
DOI：
10.1016/s1470-2045(18)30242-0
发表时间：
2018-06
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Waszak SM;Northcott PA;Buchhalter I;Robinson GW;Sutter C;Groebner S;Grund KB;Brugières L;Jones DTW;Pajtler KW;Morrissy AS;Kool M;Sturm D;Chavez L;Ernst A;Brabetz S;Hain M;Zichner T;Segura-Wang M;Weischenfeldt J;Rausch T;Mardin BR;Zhou X;Baciu C;Lawerenz C;Chan JA;Varlet P;Guerrini-Rousseau L;Fults DW;Grajkowska W;Hauser P;Jabado N;Ra YS;Zitterbart K;Shringarpure SS;De La Vega FM;Bustamante CD;Ng HK;Perry A;MacDonald TJ;Hernáiz Driever P;Bendel AE;Bowers DC;McCowage G;Chintagumpala MM;Cohn R;Hassall T;Fleischhack G;Eggen T;Wesenberg F;Feychting M;Lannering B;Schüz J;Johansen C;Andersen TV;Röösli M;Kuehni CE;Grotzer M;Kjaerheim K;Monoranu CM;Archer TC;Duke E;Pomeroy SL;Shelagh R;Frank S;Sumerauer D;Scheurlen W;Ryzhova MV;Milde T;Kratz CP;Samuel D;Zhang J;Solomon DA;Marra M;Eils R;Bartram CR;von Hoff K;Rutkowski S;Ramaswamy V;Gilbertson RJ;Korshunov A;Taylor MD;Lichter P;Malkin D;Gajjar A;Korbel JO;Pfister SM
通讯作者：
Pfister SM