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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date χ Τ It ί Λ ί 1 September 2011 (01.09.2011) WO 2U11/1U473U Al (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, CI2Q 1/68 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/IS201 1/050004 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 24 February 201 1 (24.02.201 1) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Langi English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 24 February 2010 (24.02.2010) IS ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant (for all designated States except US): DE¬ EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, CODE GENETICS EHF [IS/IS]; Sturlugata 8, Reyk LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, javik, IS-101 Reykjavik (IS). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/ Applicants (for US only): GUDBJARTSSON, Declarations under Rule 4.17 : Daniel [IS/IS]; Sogavegur 38, IS-108 Reykjavik (IS). — of inventorship (Rule 4.1 7(iv)) RAFNAR, Thorunn [IS/IS]; Kvistaland 24, IS-108 Reykjavik (IS). THORGEIRSSON, Thorgeir [IS/IS]; Published: Vesturgata 5a, IS-101 Reykjavik (IS). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, © o o (54) Title: GENETIC VARIANTS PREDICTIVE OF LUNG CANCER RISK (57) Abstract: The present invention discloses certain genetic variants that are susceptibility variants for lung cancer. The inven tion relates to risk assessment and diagnostic methods using the variants. The invention further relates to kits for use in risk assess ment of lung cancer. GENETIC VARIANTS PREDICTIVE OF LUNG CANCER RISK BACKGROUND OF THE INVENTION Genetic risk is conferred by subtle differences in the genome among individuals in a popu lation . Variations in the hu man genome are most frequently due to single nucleotide polymorphisms (SNPs), although other variations are also importa nt. SNPs are located on average every 1000 base pai rs in the huma n genome. According ly, a typica l hu man gene containing 250,000 base pairs may contain 250 different SNPs. Only a minor nu mber of SNPs are located in exons and alter the amino acid sequence of the protei n encoded by the gene . Most SNPs may have little or no effect on gene function, while others may alter tra nscription, splicing, translation, or sta bility of the mRNA encoded by the gene. Additional genetic polymorphisms in the human genome are caused by insertions, deletions, tra nslocations or inversion of either short or long stretches of DNA. Genetic polymorphisms conferring disease risk may directly alter the amino acid sequence of proteins, may increase the amou nt of protein produced from the gene, or may decrease the amount of protein produced by the gene. As genetic polymorphisms conferring risk of common diseases are uncovered, genetic testing for such risk factors is becoming increasingly important for clinica l medicine. Examples are apoli poprotein E testing to identify genetic carriers of the apoE4 polymorphism in dementia patients for the differentia l diagnosis of Alzheimer's disease, and of Factor V Leiden testing for predisposition to deep venous thrombosis. More importantly, in the treatment of ca ncer, diagnosis of genetic variants in t umor cel ls is used for the selection of the most appropriate treatment regime for the individua l patient. I n breast cancer, genetic variation in estrogen receptor expression or heregu lin type 2 (Her2) receptor tyrosine kinase expression determine if anti-estrogenic drugs (tamoxifen) or anti-Her2 anti body (Herceptin) will be incorporated into the treatment pla n. I n chronic myeloid leu kemia (CML) diag nosis of the Philadelphia chromosome genetic translocation fusing the genes encoding the Bcr and Abl receptor tyrosine kinases indicates that Gleevec (STI57 1), a specific inhibitor of the Bcr-Abl kinase shou ld be used for treatment of the cancer. For CML patients with such a genetic alteration, inhibition of the Bcr- Abl kinase leads to rapid elimination of the t umor cells and remission from leu kemia . Furthermore, genetic testing services are now available, providing individuals with information about their disease risk based on the discovery that certai n SNPs have been associated with risk of many of the common diseases. Lu ng cancer causes more deaths from cancer worldwide tha n any other form of ca ncer (Goodman, G.E., Thorax 57: 994-999 (2002)) . I n the United States, lu ng ca ncer is the prima ry cause of cancer death among both men and women . I n 2007, the death rate from lung cancer was an estimated 160,390 deaths, exceeding the combined tota l for breast, prostate and colon cancer (America Cancer Society, www.cancer.org) . Lu ng cancer is also the leadi ng cause of cancer death in all Eu ropea n cou ntries and is ra pid ly increasing in developing cou ntries. While environ mental factors, such as lifestyle factors (e.g. , smoking) and dieta ry factors, play an importa nt role in lung cancer, genetic factors also contribute to the disease . For exa mple, a family of enzymes responsible for carcinogen activation, degradation and subsequent DNA repair have been implicated in susceptibi lity to lung cancer. I n addition, an increased risk to familial members outside of the nuclear family has been shown by deCODE geneticists by ana lysing all lu ng ca ncer cases diagnosed in Icela nd over 48 yea rs. This increased risk could not be entirely accou nted for by smoking indicating that genetic variants may predispose certain individuals to lu ng ca ncer (Jonsson et.al. , JAMA 292(24) :2977-83 (2004) ; Amundadottir et.al., PLoS Med. I (3) :e65 (2004)) . The five-year survival rate among all lu ng ca ncer patients, regard less of the stage of disease at diagnosis, is only 13% . This contrasts with a five-yea r survival rate of 46% among cases detected while the disease is still localized . However, only 16% of lu ng ca ncers are discovered before the disease has spread . Early detection is difficu lt as clinical symptoms are often not observed until the disease has reached an advanced stage. Cu rrently, diagnosis is aided by the use of chest x-rays, analysis of the type of cells contained in sputu m and fiberoptic exa mination of the bronchial passages. Treatment regimens are determined by the type and stage of the cancer, and include surgery, radiation therapy and/or chemotherapy. I n spite of considerable research into therapies for this and other cancers, lu ng cancer remains difficult to diagnose and treat effectively. Accordingly, there is a great need in the art for improved methods for detecting and treating such ca ncers. Smoking of tobacco products, and in particular cigarettes, is the largest known risk factor lu ng cancer with a global attri buta ble proportion estimated to be approximately 90% in men and 80% in women . Although the risk of lu ng cancer associated with tobacco smoking is strongly related to duration of smoking, and declines with increasing time from cessation, the estimated lifetime risk of lung cancer among former smokers remains high, ranging from approximately 6% in smokers who give up at the age of 50, to 10% for smokers who give up at age 60, com pared to 15% for lifelong smokers and less than 1% in never-smokers (Peto et al. 2000 BMJ, 321, 323- 32, Bren nan, et al. 2006 Am J Epidemiol 164, 1233- 1241) . I n populations where the large majority of smokers have quit smoking, such as men in the US and UK, the majority of lung cancer cases now occu rs among ex-smokers (Doll et al. 1994 BMJ 309, 901-91 1, Zhu et al. 2001 Ca ncer Res, 61, 7825-7829) . This emphasizes the importance of developing alternative prevention measu res for lung cancer including the identification of high risk subgrou ps. Nota bly, only about 15% of lifelong smokers wil l develop lu ng cancer by the age of 75, and approximately 5 to 10% of lifetime smokers will develop another tobacco-related cancer (Kjaerheim et al. 1998 Cancer Causes Control 9, 99- 108) . A possible explanation for this large differences in risk for individua ls with similar level of tobacco exposures could be that genetic factors play a determining role in lu ng cancer susceptibility (Spitz et al. 2005 J Clin Oncol 23, 267-275) . Identifying genes, which influence the risk of lu ng ca ncer, cou ld be important for severa l aspects of management of the disease.