From Genome to Life:

SPINOLA Monica

Istituto Nazionale Tumori, Operative Unit "Polygenic Inheritance", Via Venezian 1, Milan 20133, Italy

title: Case-only association studies to identify functional polymorphisms affecting tumor prognosis

The LMYC1 gene maps in a chromosomal region for which genetic polymorphisms and loss of heterozigosity (LOH) have been reported to be associated with cancer prognosis. An intragenic EcoRI restriction site polymorphism of this proto-oncogene was significantly associated with lung tumor prognosis in Japanese and Chinese but not in Caucasian populations. These contrasting findings might be due to differences in the linkage disequilibrium (LD) pattern among populations or to confounding effects, such as sample size and histotype differences, that might have obscured any meaningful association. To further investigate this discrepancy we used single nucleotide polymorphisms (SNPs) to perform association studies with tumor prognosis of Italian and Japanese non-small cell lung cancer (NSCLC) patients. Screening of LMYC1 sequence in an Italian subgroup allowed the identification of two additional SNPs in the 3’-UTR of the gene, but no coding polymorphism was found. The newly discovered genetic markers were not present in the Japanese group we analyzed. No significant association was found between any of the three SNPs and lung-tumor prognosis in Italian patients. Moreover, significant LD between EcoRI and the two other SNPs was detected in the Italian population, whereas the two 3’-UTR markers displayed no significant LD despite their close proximity. The population-specific LD pattern we found in our study might represent a possible explanation for the contrasting results observed between Asian and Caucasian populations, suggesting that the EcoRI polymorphism could be in LD with a nearby gene that may affect lung tumor prognosis but significant LD is detectable only in Asians.