Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

被引：141

作者：

Archambault, Alexi N. ^{[1
]}

Su, Yu-Ru ^{[2
]}

Jeon, Jihyoun ^{[3
]}

Thomas, Minta ^{[2
]}

Lin, Yi ^{[2
]}

Conti, David V. ^{[4
]}

Win, Aung Ko ^{[5
]}

Sakoda, Lori C. ^{[2
,6
]}

Lansdorp-Vogelaar, Iris ^{[7
]}

Peterse, Elisabeth F. P. ^{[7
]}

Zauber, Ann G. ^{[8
]}

Duggan, David ^{[9
]}

Holowatyj, Andreana N. ^{[10
,11
]}

Huyghe, Jeroen R. ^{[2
]}

Brenner, Hermann ^{[12
,13
,14
,15
]}

Cotterchio, Michelle ^{[16
]}

Bezieau, Stephane ^{[17
]}

Schmit, Stephanie L. ^{[4
,18
]}

Edlund, Christopher K. ^{[4
]}

Southey, Melissa C. ^{[19
]}

MacInnis, Robert J. ^{[5
,20
]}

Campbell, Peter T. ^{[21
]}

Chang-Claude, Jenny ^{[22
,23
]}

Slattery, Martha L. ^{[24
]}

Chan, Andrew T. ^{[25
,26
,27
,28
,29
,30
,31
]}

Joshi, Amit D. ^{[26
,28
,30
]}

Song, Mingyang ^{[32
]}

Cao, Yin ^{[26
,28
,33
]}

Woods, Michael O. ^{[34
]}

White, Emily ^{[2
,35
]}

Weinstein, Stephanie J. ^{[36
]}

Ulrich, Cornelia M. ^{[37
,38
]}

Hoffmeister, Michael ^{[12
]}

Bien, Stephanie A. ^{[2
]}

Harrison, Tabitha A. ^{[2
]}

Hampe, Jochen ^{[39
]}

Li, Christopher I. ^{[2
]}

Schafmayer, Clemens ^{[40
]}

Offit, Kenneth ^{[41
,42
]}

Pharoah, Paul D. ^{[43
]}

Moreno, Victor ^{[44
,45
,46
]}

Lindblom, Annika ^{[47
,48
]}

Wolk, Alicja ^{[49
]}

Wu, Anna H. ^{[4
]}

Li, Li ^{[50
]}

Gunter, Marc J. ^{[51
]}

Gsur, Andrea ^{[52
]}

Keku, Temitope O. ^{[53
]}

Pearlman, Rachel ^{[54
]}

Bishop, D. Timothy ^{[55
]}

机构：

[1] NYU, Div Epidemiol, Dept Populat Hlth, Sch Med, New York, NY 10012 USA

[2] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[3] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[4] Univ Southern Calif, USC Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90007 USA

[5] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia

[6] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA

[7] Erasmus MC, Univ Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands

[8] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[9] Translat Genom Res Inst, Phoenix, AZ USA

[10] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[11] Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT USA

[12] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[13] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany

[14] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[15] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[16] Canc Care Ontario, Populat Hlth & Prevent, Toronto, ON, Canada

[17] CHU Nantes, Serv Genet Med, Nantes, France

[18] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[19] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic, Australia

[20] Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia

[21] Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA USA

[22] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[23] UCCH, Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany

[24] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA

[25] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[26] Harvard Med Sch, Boston, MA 02115 USA

[27] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[28] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA USA

[29] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[30] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[31] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[32] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[33] Washington Univ, Div Publ Hlth Sci, Dept Surg, St Louis, MO 63110 USA

[34] Mem Univ Newfoundland, Discipline Genet, St John, NF, Canada

[35] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA

[36] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[37] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[38] Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT USA

[39] Tech Univ Dresden, Univ Hosp Dresden, Dept Med 1, Dresden, Germany

[40] Univ Hosp Schleswig Holstein, Dept Gen & Thorac Surg, Campus Kiel, Kiel, Germany

[41] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA

[42] Weill Cornell Med Coll, Dept Med, New York, NY USA

[43] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[44] Catalan Inst Oncol IDIBELL, Canc Prevent & Control Program, Barcelona, Spain

[45] CIBERESP, Madrid, Spain

[46] Univ Barcelona, Fac Med, Dept Clin Sci, Barcelona, Spain

[47] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden

[48] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[49] Karolinska Inst, Inst Environm Med, Stockholm, Sweden

[50] Univ Virginia, Dept Family Med, Charlottesville, VA USA

来源：

GASTROENTEROLOGY | 2020年 / 158卷 / 05期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

Colon Cancer; SNP; Penetrance; EOCRC; GENOME-WIDE ASSOCIATION; LOW-PENETRANCE SUSCEPTIBILITY; EPIDEMIOLOGY RESEARCH; LYNCH-SYNDROME; ADULT HEALTH; TASK-FORCE; RACE/ETHNICITY; HERITABILITY; COLONOSCOPY; HEREDITARY;

D O I：

10.1053/j.gastro.2019.12.012

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 x 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.

引用

页码：1274 / +

页数：25

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