Genetic architectures of proximal and distal colorectal cancer are partly distinct
Authors: Huyghe Jeroen R , Harrison Tabitha A , Bien Stephanie A , Hampel Heather , Figueiredo Jane C , Schmit Stephanie L , Conti David V , Chen Sai , Qu Conghui , Lin Yi , Barfield Richard , Baron John A , Cross Amanda J , Diergaarde Brenda , Duggan David , Harlid Sophia , Imaz Liher , Kang Hyun Min , Levine David M , Perduca Vittorio , Perez-Cornago Aurora , Sakoda Lori C , Schumacher Fredrick R , Slattery Martha L , Toland Amanda E , van Duijnhoven Franzel JB , Van Guelpen Bethany , Arndt Volker , Agudo Antonio , Albanes Demetrius , Alonso M Henar , Anderson Kristin , Arnau-Collell Coral , Banbury Barbara , Bassik Michael C , Berndt Sonja I , Bézieau Stéphane , Bishop D Timothy , Boehm Juergen , Boeing Heiner , Boutron-Ruault Marie-Christine , Brenner Hermann , Brezina Stefanie , Buch Stephan , Buchanan Daniel D , Burnett-Hartman Andrea , Caan Bette J , Campbell Peter T , Carr Prudence , Castells Antoni , Castellví-Bel Sergi , Chan Andrew T , Chang-Claude Jenny , Chanock Stephen J , Curtis Keith R , de la Chapelle Albert , Easton Douglas F , English Dallas R , Feskens Edith JM , Gala Manish , Gallinger Steven J , Gauderman W James , Giles Graham G , Goodman Phyllis J , Grady William M , Grove John S , Gsur Andrea , Gunter Marc J , Haile Robert W , Hampe Jochen , Hoffmeister Michael , Hopper John L , Hsu Wan-Ling , Huang Wen-Yi , Hudson Thomas J , Jenab Mazda , Jenkins Mark A , Joshi Amit D , Keku Temitope O , Kooperberg Charles , Kuhn Tilman , Küry Sébastien , Le Marchand Loic , Lejbkowicz Flavio , Li Christopher I , Li Li , Lieb Wolfgang , Lindblom Annika , Lindor Noralane M , Männistö Satu , Markowitz Sanford D , Milne Roger L , Moreno Lorena , Murphy Neil , Nassir Rami , Offit Kenneth , Ogino Shuji , Panico Salvatore , Parfrey Patrick S , Pearlman Rachel , Pharoah Paul D P , Phipps Amanda I , Platz Elizabeth A , Potter John D , Prentice Ross L , Qi Lihong , Raskin Leon , Rennert Gad , Rennert Hedy S , Riboli Elio , Schafmayer Clemens , Schoen Robert E , Seminara Daniela , Song Mingyang , Su Yu-Ru , Tangen Catherine M , Thibodeau Stephen N , Thomas Duncan C , Trichopoulou Antonia , Ulrich Cornelia M , Visvanathan Kala , Vodicka Pavel , Vodickova Ludmila , Vymetalkova Veronika , Weigl Korbinian , Weinstein Stephanie J , White Emily , Wolk Alicja , Woods Michael O , Wu Anna H , Abecasis Goncalo R , Nickerson Deborah A , Scacheri Peter C , Kundaje Anshul , Casey Graham , Gruber Stephen B , Hsu Li , Moreno Victor , Hayes Richard B , Newcomb Polly A , Peters Ulrike 
Published: May 2020

ABSTRACTObjectiveAn understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for sporadic CRC differs by anatomical subsite of the primary tumor has not been examined.DesignTo identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling.ResultsWe identified 13 loci that reached genome-wide significance (P<5×10−8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.ConclusionGenetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor.Significance of this studyWhat is already known about this subject?Heterogeneity among colorectal cancer (CRC) tumors originating at different locations of the colorectum has been revealed in somatic genomes, epigenomes, and transcriptomes, and in some established environmental risk factors for CRC.Genome-wide association studies (GWAS) have identified over 100 genetic variants for overall CRC risk; however, a comprehensive analysis of the extent to which genetic risk factors differ by the anatomical sublocation of the primary tumor is lacking.What are the new findings?In this large consortium-based study, we analyzed clinical and genome-wide genotype data of 112,373 CRC cases and controls of European ancestry to comprehensively examine whether CRC case subgroups defined by anatomical sublocation have distinct germline genetic etiologies.We discovered 13 new loci at genome-wide significance (P<5×10−8) that were specific to certain anatomical sublocations and that were not reported by previous GWAS for overall CRC risk; multiple lines of evidence support strong candidate target genes at several of these loci, including PTGER3, LCT, MLH1, CDX1, KLF14, PYGL, BCL11B, and BMP7.Systematic heterogeneity analysis of genetic risk variants for CRC identified thus far, revealed that the genetic architectures of proximal and distal CRC are partly distinct.Taken together, our results further support the idea that tumors arising in different anatomical sublocations of the colorectum may have distinct etiologies.How might it impact on clinical practice in the foreseeable future?Our results provide an informative resource for understanding the differential role that genes and pathways may play in the mechanisms of proximal and distal CRC carcinogenesis.The new insights into the etiologies of proximal and distal CRC may inform the development of new precision prevention strategies, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention.Our findings suggest that future studies of etiological risk factors for CRC and molecular mechanisms of carcinogenesis should take into consideration the anatomical sublocation of the colorectal tumor.