Abstract 2017: Galectin-3 SNP rs10148371 in the anti-death motif NWGR is related to the colon cancer incidence in African Americans
Authors: Pratima Nangia-Makker, Ikuko Kato, Tirza Raz, Balan Vitaly, Avraham Raz
Journal: Cancer Research (2012)

Abstract Survival after cancer diagnosis is poorer for African Americans than for Caucasians. While some of this survival difference is driven by differences in the stage at diagnosis, even within the stage this trend is evident. For example, 5-year relative survival for colorectal cancer diagnosed as regional stage is 68.5% for Caucasians and only 60.6% for African Americans. Little is known about racial differences in response to chemotherapy and the subsequent impact on survival. A number of recent reports have focused on single nucleotide polymorphisms (SNPs) with the notion that such genetic event(s) can/may contribute to cancer development or progression. We have identified a SNP, rs10148371, which results in the substitution of R183K in the NWGR anti-death motif of the galectin-3 gene. Galectin-3, belonging to the family of carbohydrate-binding galectins is a multi-function tumor associated protein, which regulates cell growth, cell proliferation, cell adhesion, angiogenesis and apoptosis. It contains the NWGR motif characteristic of BH1 domain of Bcl-2 family responsible for protecting cells from apoptosis. To understand the significance of this SNP, we generated point mutation G548 to A in galectin-3 cDNA leading to R183K substitution. The resulting cDNA was stably transfected into low galectin-3 expressing colon carcinoma cells SW480 and RKO. Selected clones were analyzed for cell survival and apoptotic potential against cisplatin, 5 fluoro-uracil and oxaliplatin. The clones containing mutated galectin-3 showed a higher susceptibility to apoptosis compared to the wild type galectin-3. The WT clones showed an up-regulation of β-catenin and its downstream target proteins, which was not seen in the mutant clones. Ability/inability of mutated galectin-3 in the nuclear translocation of β-catenin is being studied. The racial distribution of the SNP rs10148371 in the normal population of the African Americans is 22%, while in Caucasians and Asians disease free population it can be found in less than 1%. To analyze the significance of this SNP in relation to breast and colorectal cancer, we performed genotype analysis with breast cancer (N=124) or colorectal cancer (N=129) patients. Stratified analyses revealed that the Lys variant was marginally significantly inversely associated with advanced tumor stage (p=0.08) and younger (&amp;lt;50 years for breast cancer and &amp;lt;60 years for colorectal) onset (p=0.05). However, survival did not show that this variant was associated with the risk of overall deaths (hazard ratio 0.79 (95% confidence interval: 0.40-1.56)). Next, we analyzed if the variations in genotype distribution can be related to sex in colorectal cancer. We saw a significant increase in the percent of Lysine harboring males with colorectal cancer. The Chi-Square probability was 0.0509. Albeit not a dramatic difference but certainly suggestive, which will require further study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2017. doi:1538-7445.AM2012-2017