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Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.
Gastroenterology ( IF 25.7 ) Pub Date : 2019-12-19 , DOI: 10.1053/j.gastro.2019.12.012 Alexi N Archambault 1 , Yu-Ru Su 2 , Jihyoun Jeon 3 , Minta Thomas 2 , Yi Lin 2 , David V Conti 4 , Aung Ko Win 5 , Lori C Sakoda 6 , Iris Lansdorp-Vogelaar 7 , Elisabeth F P Peterse 7 , Ann G Zauber 8 , David Duggan 9 , Andreana N Holowatyj 10 , Jeroen R Huyghe 2 , Hermann Brenner 11 , Michelle Cotterchio 12 , Stéphane Bézieau 13 , Stephanie L Schmit 14 , Christopher K Edlund 4 , Melissa C Southey 15 , Robert J MacInnis 16 , Peter T Campbell 17 , Jenny Chang-Claude 18 , Martha L Slattery 19 , Andrew T Chan 20 , Amit D Joshi 21 , Mingyang Song 22 , Yin Cao 23 , Michael O Woods 24 , Emily White 25 , Stephanie J Weinstein 26 , Cornelia M Ulrich 10 , Michael Hoffmeister 27 , Stephanie A Bien 2 , Tabitha A Harrison 2 , Jochen Hampe 28 , Christopher I Li 2 , Clemens Schafmayer 29 , Kenneth Offit 30 , Paul D Pharoah 31 , Victor Moreno 32 , Annika Lindblom 33 , Alicja Wolk 34 , Anna H Wu 4 , Li Li 35 , Marc J Gunter 36 , Andrea Gsur 37 , Temitope O Keku 38 , Rachel Pearlman 39 , D Timothy Bishop 40 , Sergi Castellví-Bel 41 , Leticia Moreira 41 , Pavel Vodicka 42 , Ellen Kampman 43 , Graham G Giles 44 , Demetrius Albanes 45 , John A Baron 46 , Sonja I Berndt 45 , Stefanie Brezina 37 , Stephan Buch 10 , Daniel D Buchanan 47 , Antonia Trichopoulou 48 , Gianluca Severi 49 , María-Dolores Chirlaque 50 , Maria-José Sánchez 51 , Domenico Palli 52 , Tilman Kühn 53 , Neil Murphy 54 , Amanda J Cross 55 , Andrea N Burnett-Hartman 56 , Stephen J Chanock 45 , Albert de la Chapelle 57 , Douglas F Easton 58 , Faye Elliott 40 , Dallas R English 44 , Edith J M Feskens 43 , Liesel M FitzGerald 59 , Phyllis J Goodman 60 , John L Hopper 61 , Thomas J Hudson 62 , David J Hunter 63 , Eric J Jacobs 17 , Corinne E Joshu 64 , Sébastien Küry 65 , Sanford D Markowitz 34 , Roger L Milne 16 , Elizabeth A Platz 64 , Gad Rennert 66 , Hedy S Rennert 66 , Fredrick R Schumacher 67 , Robert S Sandler 38 , Daniela Seminara 68 , Catherine M Tangen 60 , Stephen N Thibodeau 69 , Amanda E Toland 57 , Franzel J B van Duijnhoven 43 , Kala Visvanathan 64 , Ludmila Vodickova 42 , John D Potter 2 , Satu Männistö 70 , Korbinian Weigl 71 , Jane Figueiredo 72 , Vicente Martín 73 , Susanna C Larsson 74 , Patrick S Parfrey 75 , Wen-Yi Huang 26 , Heinz-Josef Lenz 76 , Jose E Castelao 77 , Manuela Gago-Dominguez 78 , Victor Muñoz-Garzón 79 , Christoph Mancao 80 , Christopher A Haiman 4 , Lynne R Wilkens 81 , Erin Siegel 82 , Elizabeth Barry 83 , Ban Younghusband 24 , Bethany Van Guelpen 84 , Sophia Harlid 85 , Anne Zeleniuch-Jacquotte 1 , Peter S Liang 86 , Mengmeng Du 8 , Graham Casey 87 , Noralane M Lindor 88 , Loic Le Marchand 81 , Steven J Gallinger 89 , Mark A Jenkins 5 , Polly A Newcomb 90 , Stephen B Gruber 91 , Robert E Schoen 92 , Heather Hampel 39 , Douglas A Corley 93 , Li Hsu 94 , Ulrike Peters 95 , Richard B Hayes 1
Gastroenterology ( IF 25.7 ) Pub Date : 2019-12-19 , DOI: 10.1053/j.gastro.2019.12.012 Alexi N Archambault 1 , Yu-Ru Su 2 , Jihyoun Jeon 3 , Minta Thomas 2 , Yi Lin 2 , David V Conti 4 , Aung Ko Win 5 , Lori C Sakoda 6 , Iris Lansdorp-Vogelaar 7 , Elisabeth F P Peterse 7 , Ann G Zauber 8 , David Duggan 9 , Andreana N Holowatyj 10 , Jeroen R Huyghe 2 , Hermann Brenner 11 , Michelle Cotterchio 12 , Stéphane Bézieau 13 , Stephanie L Schmit 14 , Christopher K Edlund 4 , Melissa C Southey 15 , Robert J MacInnis 16 , Peter T Campbell 17 , Jenny Chang-Claude 18 , Martha L Slattery 19 , Andrew T Chan 20 , Amit D Joshi 21 , Mingyang Song 22 , Yin Cao 23 , Michael O Woods 24 , Emily White 25 , Stephanie J Weinstein 26 , Cornelia M Ulrich 10 , Michael Hoffmeister 27 , Stephanie A Bien 2 , Tabitha A Harrison 2 , Jochen Hampe 28 , Christopher I Li 2 , Clemens Schafmayer 29 , Kenneth Offit 30 , Paul D Pharoah 31 , Victor Moreno 32 , Annika Lindblom 33 , Alicja Wolk 34 , Anna H Wu 4 , Li Li 35 , Marc J Gunter 36 , Andrea Gsur 37 , Temitope O Keku 38 , Rachel Pearlman 39 , D Timothy Bishop 40 , Sergi Castellví-Bel 41 , Leticia Moreira 41 , Pavel Vodicka 42 , Ellen Kampman 43 , Graham G Giles 44 , Demetrius Albanes 45 , John A Baron 46 , Sonja I Berndt 45 , Stefanie Brezina 37 , Stephan Buch 10 , Daniel D Buchanan 47 , Antonia Trichopoulou 48 , Gianluca Severi 49 , María-Dolores Chirlaque 50 , Maria-José Sánchez 51 , Domenico Palli 52 , Tilman Kühn 53 , Neil Murphy 54 , Amanda J Cross 55 , Andrea N Burnett-Hartman 56 , Stephen J Chanock 45 , Albert de la Chapelle 57 , Douglas F Easton 58 , Faye Elliott 40 , Dallas R English 44 , Edith J M Feskens 43 , Liesel M FitzGerald 59 , Phyllis J Goodman 60 , John L Hopper 61 , Thomas J Hudson 62 , David J Hunter 63 , Eric J Jacobs 17 , Corinne E Joshu 64 , Sébastien Küry 65 , Sanford D Markowitz 34 , Roger L Milne 16 , Elizabeth A Platz 64 , Gad Rennert 66 , Hedy S Rennert 66 , Fredrick R Schumacher 67 , Robert S Sandler 38 , Daniela Seminara 68 , Catherine M Tangen 60 , Stephen N Thibodeau 69 , Amanda E Toland 57 , Franzel J B van Duijnhoven 43 , Kala Visvanathan 64 , Ludmila Vodickova 42 , John D Potter 2 , Satu Männistö 70 , Korbinian Weigl 71 , Jane Figueiredo 72 , Vicente Martín 73 , Susanna C Larsson 74 , Patrick S Parfrey 75 , Wen-Yi Huang 26 , Heinz-Josef Lenz 76 , Jose E Castelao 77 , Manuela Gago-Dominguez 78 , Victor Muñoz-Garzón 79 , Christoph Mancao 80 , Christopher A Haiman 4 , Lynne R Wilkens 81 , Erin Siegel 82 , Elizabeth Barry 83 , Ban Younghusband 24 , Bethany Van Guelpen 84 , Sophia Harlid 85 , Anne Zeleniuch-Jacquotte 1 , Peter S Liang 86 , Mengmeng Du 8 , Graham Casey 87 , Noralane M Lindor 88 , Loic Le Marchand 81 , Steven J Gallinger 89 , Mark A Jenkins 5 , Polly A Newcomb 90 , Stephen B Gruber 91 , Robert E Schoen 92 , Heather Hampel 39 , Douglas A Corley 93 , Li Hsu 94 , Ulrike Peters 95 , Richard B Hayes 1
Affiliation
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BACKGROUND & AIMS
Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.
METHODS
We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.
RESULTS
Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.
CONCLUSIONS
In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
中文翻译：
结直肠癌相关基因变异的累积负担与早发性癌症与晚发性癌症的相关性更强。
背景与目的 早发性结直肠癌（CRC，50 岁以下人群）的发病率正在增加；然而，由于没有 CRC 家族史，该人群缺乏统一的预防建议。我们的目的是确定从 95 个 CRC 相关的常见遗传风险变异中得出的多基因风险评分 (PRS) 是否与早发 CRC 风险相关。方法 我们研究了 12,197 名 50 岁以下参与者与 95,865 名 50 岁或以上参与者的加权 PRS 相关的 CRC 风险。 PRS 是根据截至 2019 年 1 月的一项大规模全基因组关联研究中与 CRC 相关的单核苷酸多态性计算的。参与者来自提供临床和基因分型数据的 3 个大型联盟：结肠癌家族登记处、结直肠跨学科研究、结直肠癌遗传学和流行病学联盟的成员均具有基因定义的欧洲血统。研究结果在 72,573 名参与者的独立队列中得到了重复。结果 对于早发性癌症，每 PRS 标准差与 CRC 的整体关联性显着，并且与晚发性癌症相比更强（交互作用 P = 0.01）；当我们将最高 PRS 四分位与最低 PRS 四分位数进行比较时，早发 CRC 的风险增加了 3.7 倍（95% CI 3.28-4.24），而晚发 CRC 的风险增加了 2.9 倍（95% CI 2.80-3.04）。对于没有 CRC 一级家族史的参与者，这种关联最为强烈（交互作用 P = 5.61 × 10-5）。当我们比较该组中最高和最低四分位数时，早发性 CRC 的风险增加了 4.3 倍（95% CI 3.61-5.01），而晚发性 CRC 的风险增加了 2.9 倍（95% CI 2.70-3.00）。敏感性分析与这些发现一致。 结论 在根据 PRS 标准差对 CRC 关联进行分析时，我们发现 CRC 相关常见遗传变异的累积负担与早发性癌症相关，并且与早发性癌症的相关性比晚发性癌症的相关性更强。特别是在没有 CRC 家族史的情况下。对 PRS 以及环境和生活方式风险因素的分析可能会识别出可以从预防措施中受益的年轻人。
更新日期：2020-04-21
中文翻译：
结直肠癌相关基因变异的累积负担与早发性癌症与晚发性癌症的相关性更强。
背景与目的 早发性结直肠癌（CRC，50 岁以下人群）的发病率正在增加；然而，由于没有 CRC 家族史，该人群缺乏统一的预防建议。我们的目的是确定从 95 个 CRC 相关的常见遗传风险变异中得出的多基因风险评分 (PRS) 是否与早发 CRC 风险相关。方法 我们研究了 12,197 名 50 岁以下参与者与 95,865 名 50 岁或以上参与者的加权 PRS 相关的 CRC 风险。 PRS 是根据截至 2019 年 1 月的一项大规模全基因组关联研究中与 CRC 相关的单核苷酸多态性计算的。参与者来自提供临床和基因分型数据的 3 个大型联盟：结肠癌家族登记处、结直肠跨学科研究、结直肠癌遗传学和流行病学联盟的成员均具有基因定义的欧洲血统。研究结果在 72,573 名参与者的独立队列中得到了重复。结果 对于早发性癌症，每 PRS 标准差与 CRC 的整体关联性显着，并且与晚发性癌症相比更强（交互作用 P = 0.01）；当我们将最高 PRS 四分位与最低 PRS 四分位数进行比较时，早发 CRC 的风险增加了 3.7 倍（95% CI 3.28-4.24），而晚发 CRC 的风险增加了 2.9 倍（95% CI 2.80-3.04）。对于没有 CRC 一级家族史的参与者，这种关联最为强烈（交互作用 P = 5.61 × 10-5）。当我们比较该组中最高和最低四分位数时，早发性 CRC 的风险增加了 4.3 倍（95% CI 3.61-5.01），而晚发性 CRC 的风险增加了 2.9 倍（95% CI 2.70-3.00）。敏感性分析与这些发现一致。 结论 在根据 PRS 标准差对 CRC 关联进行分析时，我们发现 CRC 相关常见遗传变异的累积负担与早发性癌症相关，并且与早发性癌症的相关性比晚发性癌症的相关性更强。特别是在没有 CRC 家族史的情况下。对 PRS 以及环境和生活方式风险因素的分析可能会识别出可以从预防措施中受益的年轻人。
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