טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentFares Eman
SubjectIdentification of Genetic Markers Involved in Development
of Cancer in Israeli Druze Community
DepartmentDepartment of Medicine
Supervisors Professor Gad Rennert
Clinical Professor Walid Saliba
Full Thesis textFull thesis text - English Version


Abstract

The Druze are a unique secluded population in the Middle East. Genome-Wide-Association-International-Studies revealed novel genetic markers for breast and colorectal cancer susceptibility, but little is known about molecular variants associated with breast and colorectal cancer in the Druze Population.

The aim of the current study is to measure the prevalence of formerly reported genetic risk variants among the Druze community of different sources (Lebanon, Syria, and Israel) and to study their association with breast and colorectal cancer risk. Our study included 176 Druze participants from the Breast-Cancer-In-Northern Israel-Study (93 cases, 83 controls) and 196 participants from the Molecular- Epidemiology-Colorectal-Cancer-Study (119 cases, 77 controls). DNA was extracted from blood samples and analyzed using the Illumina OncoArray chip holding ~535,000 SNPs. We identified 83 SNPs associated with breast cancer and 43 SNPs associated with colorectal cancer.

The results indicate that the major allele frequency of: chr5_16187528_G_T and rs2380205 was higher in Caucasians than in Druze, while of rs4973768 and rs2363956 was higher in Druze than in Caucasians. Moreover, major allele frequency differed between Druze from different origins; major allele frequency of: rs10760444, rs13281615, chr16_54682064_A_G, rs2981579, rs11632715, and rs10911251 was lower in Syrian Druze. Major allele frequency of: chr8_117209548 was lower in Lebanese, while of rs6983267 and rs10505477 was higher in Lebanese Druze, and of: rs12710696 and chr5_16187528_G_T was higher in Israeli Druze.

The SNP rs10022462 in LOC105369192 was associated with increased risk of breast cancer (OR=1.71, 95%CI=1.13-2.58, P=0.01) among Druze participants. Four additional SNPs were found to be associated with decreased risk of breast cancer: chr20_5948227_A_G in GIPR: OR=0.43(0.20-0.90), chr2_218296508_C_T in DIRC3: OR=0.61(0.37-0.98), chr5_32567732_C_T: OR=0.58(0.38-0.89) and rs13387042 in CDYL2: OR=0.57(0.37-0.89). Moreover, the SNPs; rs1219648, rs2981579, and rs2981582 in the FGFR2, and chr12_1208332146_C_T, rs11627032, rs2420946 and chr19_19545696_A_G in MIR640 were significantly associated with over three-fold increased risk of HER2 positive breast cancer, while chr16_54682064_A_G was significantly associated with increased risk of TN breast cancer. Chr5_32567732_C_T was significantly associated with decreased risk of HER2 positive; while chr7_28356889_C_T and rs11627032 were significantly associated with decreased risk of TN breast cancer.  No significant association was found between 43 candidate SNPs and increased risk of colorectal cancer, but rs704017 in ZMIZ1 was significantly associated with decreased risk of MSI-high colorectal cancer.

Specifically, in Israeli Druze, chr16_54682064_A_G was found to be associated with increased risk of breast cancer and the rs3217901 in CCND2 was significantly associated with decreased risk of colorectal cancer. In Lebanese Druze, rs10022462 in LOC105369192 was associated with increased breast cancer risk, rs1957636 in LOC105370507 was significantly associated with increased risk for colorectal cancer and rs4925386 in LAMA5 was significantly associated with decreased risk of colorectal cancer. In Syrian Druze, rs59336 in TBX3 gene was significantly associated decreased risk of colorectal cancer.


Prevalence and risk pattern of the various studied variants differed between Druze and published data about Caucasians. Further to this, rates also differed between Druze of different origins. With low cancer incidence rates reported in the Druze, these findings need to be further studied for their potential mechanisms of disease risk or protection.