colorectal cancer: The Multiethnic Cohort

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colorectal cancer: The Multiethnic Cohort Abstract # 4589 Association of genes, pathways, and haplogroups of the mitochondrial genome with the risk of colorectal cancer: The Multiethnic Cohort Yuqing Li1,2, Kenneth Beckman3, Christian Caberto4, Remi Kazma 5, Annette Lum-Jones4, Christopher A. Haiman6, Loic Le Marchand4, Daniel O Stram6, Richa Saxena7,8,9, Iona Cheng1,2 Cancer Prevention Institute of California, CA1; Stanford Cancer Institute, CA2; University of Minnesota Genomics Center, MI3; University of Hawaii Cancer Center, HI4; Centre National de Génotypage, France5; University of Southern California, CA6; Massachusetts General Hospital, MA7; Harvard Medical School, MA8; The Broad Institute of Harvard and MIT, MA9 Introduction Introduction Results Results Colorectal cancer (CRC) is the third most common cancer among men and women in the United States. Approximately 35% of CRC is estimated to be attributed to inherited susceptibility. The mitochondrial genome has been understudied in genetic association studies of CRC and may harbor CRC risk variants. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the oxidative phosphorylation (OXPHOS) process, and promoting the production of reactive oxidative species. Table 2. Association between mitochondrial genome, pathways, and genes and colorectal cancer risk in European Americans Table 1. Study characteristics of 14,568 colorectal cancer cases and controls Mitochondrial genome Mitochondiral OXPHOS pathway Mitochondrial complexes Mitochondrial genes No. of mtSNPs P value q value Complex Gene 168 0.040 133 0.029 0.054 Complex I 80 0.025 0.081 MT-ND1 9 0.24 0.36 MT-ND2 14 0.001 0.015 MT-ND3 6 0.29 MT-ND4 16 0.113 MT-ND4L 3 0.43 0.48 MT-ND5 24 0.15 0.32 MT-ND6 8 0.28 Complex III 15 0.027 MT-CYB 0.135 Complex IV 28 0.198 0.297 MT-CO1 0.11 MT-CO2 5 MT-CO3 Complex V 10 0.095 0.19 MT-ATP6 MT-ATP8 2 0.036 rRNA 27 0.17 tRNA 0.10 Cases Controls n=2,498 n=12,070 Age, mean (SD) 70.4 (8.34) 68.5 (8.39) Sex, n (%) Male 1389 (55.60%) 6756 (55.97%) Female 1109 (44.40%) 5314 (44.03%) Maternal race/ethnicity, n(%) African American 475 (19.05%) 3061 (25.45%) Japanese American 824 (33.04%) 3343 (27.79%) Latinos 585 (23.46%) 2385 (19.83%) European American 489 (19.61%) 2622 (21.80%) Native Hawaiian 114 (4.57%) 598 (4.97%) BMI, n (%) <25 kg/m2 775 (37.17%) 4025 (37.62%) >=25 kg/m2 1310 (62.83.40%) 6675 (62.38%) Family history of colorectal cancer n (%) Yes 272 (11.09%) 1045 (8.83%) History of polyp of intestine, n (%) 307 (12.52%) 1078 (9.04%) Smoking, pack/year, mean (SD) 11.98 (16.29) 10.38 (14.75) Site, n (%) Colon 1870 (76.23%) Rectal 536 (21.85%) Stage, n (%) Localized 1221 (49.78) Advanced 1128 (45.98) Aim Table 3. Association between haplogroups and colorectal cancer risk in European Americans To comprehensively examine the role of the mitochondrial genome and CRC risk among African Americans, Asian Americans, European Americans, Latinos and Native Hawaiians in the Multiethnic Cohort. Results Conclusions & Future Directions Haplogroup Case/Control % OR (95%CI) P value H 34.02 / 39.91 1.00 A 1.24 / 1.59 1.21 (0.47, 3.14) 0.69 B 1.45 / 1.51 0.77 (0.25, 2.41) 0.66 HV 3.32 / 4.07 0.89 (0.48, 1.64) 0.72 I 1.04 / 1.51 0.51 (0.15, 1.69) 0.27 J 8.51 / 8.91 1.13 (0.77, 1.68) 0.52 K 9.75 / 8.49 1.33 (0.92, 1.93) 0.13 L 2.70 / 2.67 0.99 (0.47, 2.07) 0.98 N 2.90 / 2.48 1.46 (0.78, 2.73) 0.24 T 14.11 / 9.57 1.66 (1.19, 2.33) 0.003 U 14.73 / 13.33 1.31 (0.96, 1.81) 0.09 W 1.66 / 2.17 0.99 (0.46, 2.12) 0.97 X 1.24 / 1.28 1.37 (0.56, 3.35) 0.49 Freq less than 1% bin 3.32 / 2.52 1.61 (0.87, 2.99) Table 4. Association between mtSNPs in MT-ND2 and colorectal cancer risk overall and by maternal race/ethnicity Pathway based analysis demonstrated evidence of an association between the mitochondrial genome and CRC risk in the European Americans, in which the OXPHOS pathway may play an important role. Gene based analysis further suggested that MT-ND2, a member of the OXPHOS pathway that encodes for the subunit of NADH, to be associated with CRC risk in European Americans. Haplogroup T was associated with the risk of CRC risk in European Americans independent of global ancestry. There was no evidence of an association between the mitochondrial genome and CRC risk in other racial/ethnic groups. Further replication is warranted and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to CRC risk. Methods Major Allele Minor Allele MAF OR (95%CI) P* mt4917 African Americans A G 0.005 0.87 (0.20, 3.84) 0.850 Asian Americans 0.001 -- Latinos 0.006 1.89 (0.71, 5.04) 0.200 Native Hawaiians 0.002 European Americans 0.101 1.55 (1.15, 2.10) 4.00E-03 All 0.025 152 (1.16, 2.01) 2.90E-03 mt4655 0.028 1.60 (0.96,2.68) 0.070 0.86 (0.52,1.43) 0.560 8.67 (1.79,42.06) 0.007 0.016 1.22 (0.86,1.72) 0.26 mt4883 African American C T Asian American 0.347 0.95 (0.80,1.12) 0.524 0.069 0.70 (0.46,1.07) 0.102 0.012 2.66 (0.96,7.37) 0.061 0.112 0.91 (0.78,1.06) 0.21 mt5147 0.094 0.98 (0.68,1.39) 0.892 0.054 0.99 (0.69,1.41) 0.938 0.33 (0.10,1.08) 0.067 0.055 1.62 (1.11,2.38) 0.013 1.06 (0.86,1.30) 0.575 mt5178 0.348 0.539 2.52 (0.91,6.93) 0.074 0.216 619 mtSNPs information was abstracted from mtDNA sequencing data and 249 mtSNPs were validated in a multiethnic panel of 375 subjects with a minor allele frequency (MAF) greater than 1% at least in one maternal ethnic group . 185 mtSNPs were successfully genotyped in 2,453 CRC cases and 11,930 controls. The sequence kernel association test (SKAT_commonrare) was conducted to evaluate the cumulative effect of all mtDNA variants, the mtDNA OXPHOS pathway, complexes, and genes, adjusting for age, sex, and principal components of global ancestry. Unconditional logistic regression was conducted to examine the associations between haplogroup, single SNPs, and CRC risk, adjusting for age, sex and principal components of global ancestry. Stratified analyses were conducted by self-reported maternal race/ethnicity. Figure 1. Distribution of negative log of p-value of mtSNPs and colorectal cancer risk and the correlation between mt4917 and other mtSNPs in European Americans.