Methods and Compositions for Assessment of Pulmonary Function and Disorders

• US 20080286776A1
• Filed: 10/17/2007
• Published: 11/20/2008
• Est. Priority Date: 10/17/2006
• Status: Abandoned Application

• Current Assignee: Synergenz Bioscience Ltd.
• Original Assignee: Synergenz Bioscience Ltd.
• Inventors: YOUNG, Robert Peter
• Application Number:
  US11/874,187
• Publication Number:
  US 20080286776A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/172 Haplotypes

Abstract

The present invention provides methods for the assessment of risk of developing lung cancer in smokers and non-smokers using analysis of genetic polymorphisms. The present invention also relates to the use of genetic polymorphisms in assessing a subject'"'"'s risk of developing lung cancer, and the suitability of a subject for an intervention in respect of lung cancer. Nucleotide probes and primers, kits, and microarrays suitable for such assessment are also provided.

Claims

1. A method of determining a subject'"'"'s risk of developing lung cancer comprising analysing a sample from said subject for the presence or absence of one or more polymorphisms selected from the group consisting of:

Ser307Ser G/T (rsIO56503) in the X-ray repair complementing defective repair in Chinese hamster cells 4 gene,

A/T c74delA in the gene encoding cytochrome P450 polypeptide CYP3A43;

A/C (rs2279115) in the gene encoding B-cell CLL/lymphoma 2;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding Integrin beta 3;

−

3714 G/T (rs6413429) in the gene encoding Dopamine transporter 1;

A/G (rs

     1139417) in the gene encoding Tumor necrosis factor receptor 1;

C/Del (rs1799732) in the gene encoding Dopamine receptor D2;

C/T (rs763110) in the gene encoding Fas ligand;

C/T (rs5743836) in the gene encoding Toll-like receptor 9;

or

one or more polymorphisms in linkage disequilibrium with one or more of said polymorphisms, wherein the presence or absence of said polymorphism is indicative of the subject'"'"'s risk of developing lung cancer.

2. A method according to claim 1 wherein the lung cancer is selected from the group consisting of non-small cell lung cancer including adenocarcinoma and squamous cell carcinoma, small cell lung cancer, carcinoid tumor, lymphoma, or metastatic cancer.

3. A method according to claim 1 wherein the method comprises analysing said sample for the presence or absence of one or more further polymorphisms selected from the group consisting of:

R19W A/G (rs11015703) in the gene encoding Cerberus 1 (Cer

     1);

K3326X A/T (rs11571833) in the breast cancer 2 early onset gene (BRCA2);

V433M A/G (rs2306022) in the gene encoding Integrin alpha-1;

E375G T/C (rs7214723) in the gene encoding Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1);

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding Tumor protein P73 (P73);

or one or more polymorphisms which are in linkage disequilibrium with one or more of these polymorphisms.

4. A method according to any one of claims 1 to 3 wherein the presence of one or more of the polymorphisms selected from the group consisting of:

the E375G T/C TT genotype in the gene encoding CAMKK1;

the −

81 C/T (rs

     2273953) CC genotype the gene encoding P73;

the A/C (rs2279115) AA genotype in the gene encoding BCL2;

the +3100 A/G (rs2317676) AG or GG genotype in the gene encoding ITGB3;

the C/Del (rs1799732) CDel or DelDel genotype in the gene encoding DRD2;

or

the C/T (rs763110) TT genotype in the gene encoding Fas ligand;

is indicative of a reduced risk of developing lung cancer.

5. A method according to any one of claims 1 to 4 wherein the presence of one or more of the polymorphisms selected from the group consisting of:

the Ser307Ser G/T GG or GT genotype in the gene encoding XRCC4;

the R19W A/G AA or GG genotype in the gene encoding Cer 1;

the Ser307Ser G/T GG or GT genotype in the XRCC4 gene;

the K3326X A/T AT or TT genotype in the BRCA2 gene;

the V433M A/G AA genotype in the gene encoding Integrin alpha-1;

the A/T c74delA AT or TT genotype in the gene encoding CYP3A43;

the −

3714 G/T (rs6413429) GT or TT genotype in the gene encoding DAT 1;

the A/G (rs

     139417) AA genotype in the gene encoding TNFR1;

or

the C/T (rs5743836) CC genotype in the gene encoding TLR9;

is indicative of an increased risk of developing lung cancer.

6. A method according to any one of claims 1 to 3 wherein the method comprises analysing each of the polymorphisms of the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

7. A method according to any one of claims 1 to 3 wherein the method comprises analysing each of the polymorphisms of the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

8. A method according to any one of claims 1 to 3 wherein the method comprises analysing each of the polymorphisms of the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

V433M A/G (rs2306022) in the gene encoding ITGA11;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

9. A method according to any one of claims 1 to 3 wherein the method comprises analysing each of the polymorphisms of the group consisting of:

Rsa 1 C/T (rs2031920) in the gene encoding CYP 2E1;

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

−

511 A/G (rs

     16944) in the gene encoding Interleukin 1B;

V433M A/G (rs2306022) in the gene encoding ITGA11;

Arg 197 Gln A/G (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

R19W A/G (rs

     10115703) in the gene encoding Cerberus 1;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

A/G (rs1139417) in the gene encoding TNFR1;

C/T (rs5743836) in the gene encoding TLR9;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs

     1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

−

751 G/T (rs

     13181) in the promoter of the gene encoding XPD;

Phe 257 Ser C/T (rs3087386) in the gene encoding REV1;

C/T (rs763110) in the gene encoding FasL;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

17. A method according to any one of claims 1 to 16 wherein said method comprises the analysis of one or more epidemiological risk factors.

26. or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms. One or more nucleotide probes and/or primers for use in the method of any one of claims 1 to 21 wherein the one or more nucleotide probes and/or primers span, or are able to be used to span, the polymorphic regions of the genes in which the polymorphism to be analysed is present.

27. One or more nucleotide probes and/or primers as claimed in claim 26 comprising the sequence of any one of SEQ.ID.NO. 1 to SEQ.ID.NO. 72.

28. A nucleic acid microarray which comprises a substrate presenting nucleic acid sequences capable of hybridizing to nucleic acid sequences which encode one or more of the polymorphisms selected from the group defined in claim 1 or sequences complimentary thereto.

38. An antibody microarray for use in the methods as claimed in any one of claims 1 to 21 or claim 37, which microarray comprises a substrate presenting antibodies capable of binding to a product of expression of a gene the expression of which is upregulated or downregulated when associated with a susceptibility or protective polymorphism as defined in any one of claims 1 to 5.

39. A method for screening for compounds that modulate the expression and/or activity of a gene, the expression of which is upregulated or down-regulated when associated with a susceptibility or protective polymorphism selected from the group defined in any one of claims 1 to 5, said method comprising the steps of:

contacting a candidate compound with a cell comprising a susceptibility or protective polymorphism which has been determined to be associated with the upregulation or downregulation of expression of a gene; and

measuring the expression of said gene following contact with said candidate compound,

wherein a change in the level of expression after the contacting step as compared to before the contacting step is indicative of the ability of the compound to modulate the expression and/or activity of said gene.

40. A method according to claim 39 wherein said cell is a human lung cell which has been pre-screened to confirm the presence of said polymorphism.

41. A method according to claim 39 or 40 wherein said cell comprises a susceptibility polymorphism associated with upregulation of expression of said gene and said screening is for candidate compounds which down-regulate expression of said gene.

42. A method according to claim 39 or 40 wherein said cell comprises a susceptibility polymorphism associated with downregulation of expression of said gene and said screening is for candidate compounds which upregulate expression of said gene.

43. A method according to claim 39 or 40 wherein said cell comprises a protective polymorphism associated with upregulation of expression of said gene and said screening is for candidate compounds which further upregulate expression of said gene.

44. A method according to claim 39 or 40 wherein said cell comprises a protective polymorphism associated with downregulation of expression of said gene and said screening is for candidate compounds which further down-regulate expression of said gene.

45. A method for screening for compounds that modulate the expression and/or activity of a gene, the expression of which is upregulated or down-regulated when associated with a susceptibility or protective polymorphism selected from the group defined in any one of claims 1 to 5, said method comprising the steps of:

contacting a candidate compound with a cell comprising a gene, the expression of which is upregulated or downregulated when associated with a susceptibility or protective polymorphism but which in said cell the expression of which is neither upregulated nor downregulated; and

measuring the expression of said gene following contact with said candidate compound,

wherein a change in the level of expression after the contacting step as compared to before the contacting step is indicative of the ability of the compound to modulate the expression and/or activity of said gene.

46. A method according to claim 45 wherein said cell is a human lung cell which has been pre-screened to confirm the presence, and baseline level of expression, of said gene.

47. A method according to claim 45 or 46 wherein expression of the gene is downregulated when associated with a susceptibility polymorphism and said screening is for candidate compounds which, in said cell, upregulate expression of said gene.

48. A method according to claim 45 or 46 wherein expression of the gene is upregulated when associated with a susceptibility polymorphism and said screening is for candidate compounds which, in said cell, down-regulate expression of said gene.

49. A method according to claim 45 or 46 wherein expression of the gene is upregulated when associated with a protective polymorphism and said screening is for compounds which, in said cell, upregulate expression of said gene.

50. A method according to claim 45 or 46 wherein expression of the gene is downregulated when associated with a protective polymorphism and said screening is for compounds which, in said cell, downregulate expression of said gene.

51. A method of assessing the likely responsiveness of a subject predisposed to or diagnosed with lung cancer to a prophylactic or therapeutic treatment, which treatment involves restoring the physiologically active concentration of a product of gene expression to be within a range which is normal for the age and sex of the subject, which method comprises detecting in said subject the presence or absence of a susceptibility polymorphism selected from the group defined in claim 1 which when present either upregulates or down-regulates expression of said gene such that the physiological active concentration of the expressed gene product is outside said normal range, wherein the detection of the presence of said polymorphism is indicative of the subject likely responding to said treatment.

59. The method according to claim 40 wherein the result is analysed for the presence of absence of each of the polymorphisms from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

60. The method according to claim 40 wherein the result is analysed for the presence of absence of each of the polymorphisms from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

61. The method according to claim 40 wherein the result is analysed for the presence of absence of each of the polymorphisms from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

V433M A/G (rs2306022) in the gene encoding ITGA11;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

62. The method according to claim 40 wherein the result is analysed for the presence of absence of each of the polymorphisms from the group consisting of:

Rsa 1 C/T (rs2031920) in the gene encoding CYP 2E1;

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

−

511 A/G (rs

     16944) in the gene encoding Interleukin 1B;

V433M A/G (rs2306022) in the gene encoding ITGA11;

Arg 197 Gln A/G (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

R19W A/G (rs

     10115703) in the gene encoding Cerberus 1;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

A/G (rs1139417) in the gene encoding TNFR1;

C/T (rs5743836) in the gene encoding TLR9;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs

     1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

−

751 G/T (rs

     13181) in the promoter of the gene encoding XPD;

Phe 257 Ser C/T (rs3087386) in the gene encoding REV1;

C/T (rs763110) in the gene encoding FasL;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

10. A method of assessing a subject'"'"'s risk of developing lung cancer said method comprising the steps:

(i) determining the presence or absence of at least one protective polymorphism associated with a reduced risk of developing lung cancer; and

(ii) in the absence of at least one protective polymorphisms, determining the presence or absence of at least one susceptibility polymorphism associated with an increased risk of developing lung cancer;

wherein the presence of one or more of said protective polymorphisms is indicative of a reduced risk of developing lung cancer, and the absence of at least one protective polymorphism in combination with the presence of at least one susceptibility polymorphism is indicative of an increased risk of developing lung cancer.

11. A method according to claim 10 wherein said at least one protective polymorphism is selected from the group consisting of:

the E375G T/C TT genotype in the gene encoding CAMKK1;

the −

81 C/T (rs

     2273953) CC genotype the gene encoding P73;

the A/C (rs2279115) AA genotype in the gene encoding BCL2;

the +3100 A/G (rs2317676) AG or GG genotype in the gene encoding ITGB3;

the C/Del (rs1799732) CDel or DelDel genotype in the gene encoding DRD2;

or

the C/T (rs763110) TT genotype in the gene encoding Fas ligand.

12. A method according to claim 10 or 11 wherein said at least one susceptibility polymorphism is a genotype selected from the group consisting of:

the Ser307Ser G/T GG or GT genotype in the gene encoding XRCC4;

the R19W A/G AA or GG genotype in the gene encoding Cer 1;

the Ser307Ser G/T GG or GT genotype in the XRCC4 gene;

the K3326X A/T AT or TT genotype in the BRCA2 gene;

the V433M A/G AA genotype in the gene encoding Integrin alpha-1;

the A/T c74delA AT or TT genotype in the gene encoding CYP3A43;

the −

3714 G/T (rs6413429) GT or TT genotype in the gene encoding DAT 1;

the A/G (rs1139417) AA genotype in the gene encoding TNFR1;

or

the C/T (rs5743836) CC genotype in the gene encoding TLR9.

13. A method according to any one of claims 10 to 12 wherein the presence of two or more protective polymorphims irrespective of the presence of one or more susceptibility polymorphisms is indicative of reduced risk of developing lung cancer.

14. A method according to any one of claims 10 to 12 wherein in the absence of a protective polymorphism the presence of one or more susceptibility polymorphisms is indicative of an increased risk of developing lung cancer.

15. A method according to any one of claims 10 to 12 wherein the presence of two or more susceptibility polymorphisms is indicative of an increased risk of developing lung cancer.

35. A method of treating a subject having an increased risk of developing lung cancer comprising the step of replicating, genotypically or phenotypically, the presence and/or functional effect of a protective polymorphism selected from the group defined in claim 11 in said subject.

36. A method of treating a subject having an increased risk of developing lung cancer, said subject having a detectable susceptibility polymorphism selected from the group defined in claim 12 which either upregulates or down-regulates expression of a gene such that the physiologically active concentration of the expressed gene product is outside a range which is normal for the age and sex of the subject, said method comprising the step of restoring the physiologically active concentration of said product of gene expression to be within a range which is normal for the age and sex of the subject.

16. A method of determining a subject'"'"'s risk of developing lung cancer, comprising analysing a sample from said subject for the presence of two or more polymorphisms selected from the group consisting of:

the Ser307Ser G/T polymorphism in the X-ray repair complementing defective repair in Chinese hamster cells 4 gene (XRCC4);

R19W A/G in the gene encoding Cerberus 1 (Cer

     1);

K3326X A/T in the breast cancer 2 early onset gene (BRCA2);

V433M A/G in the gene encoding Integrin alpha-1;

E375G T/C in the gene encoding Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1);

A/T c74delA in the gene encoding cytochrome P450 polypeptide CYP3A43;

A/C (rs2279115) in the gene encoding B-cell CLL/lymphoma 2;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding Integrin beta 3;

−

3714 G/T (rs6413429) in the gene encoding Dopamine transporter 1;

A/G (rs

     1139417) in the gene encoding Tumor necrosis factor receptor 1;

C/Del (rs1799732) in the gene encoding Dopamine receptor D2;

C/T (rs763110) in the gene encoding Fas ligand;

C/T (rs5743836) in the gene encoding Toll-like receptor 9;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding Tumor protein P73 (P73);

or one or more polymorphisms which are in linkage disequilibrium with any one or more of these polymorphisms.

18. A method of determining a subject'"'"'s risk of developing lung cancer, said method comprising the steps:

(i) obtaining the result of one or more genetic tests of a sample from said subject; and

(ii) analysing the result for the presence or absence of one or more polymorphisms selected from the group consisting of;

Ser307Ser G/T in the X-ray repair complementing defective repair in Chinese hamster cells 4 gene (XRCC4);

A/T c74delA in the gene encoding cytochrome P450 polypeptide CYP3A43;

A/C (rs2279115) in the gene encoding B-cell CLL/lymphoma 2;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding Integrin beta 3;

−

3714 G/T (rs6413429) in the gene encoding Dopamine transporter 1;

A/G (rs1139417) in the gene encoding Tumor necrosis factor receptor 1;

C/Del (rs1799732) in the gene encoding Dopamine receptor D2;

C/T (rs763110) in the gene encoding Fas ligand;

C/T (rs5743836) in the gene encoding Toll-like receptor 9;

or one or more polymorphisms which are in linkage disequilibrium with one or more of these polymorphisms;

wherein a result indicating the presence or absence of one or more of said polymorphisms is indicative of the subject'"'"'s risk of developing lung cancer.

19. A method according to claim 18 wherein a result indicating the presence of one or more of the Ser307Ser G/T TT genotype in the gene encoding XRCC4;

the −

81 C/T (rs

     2273953) CC genotype the gene encoding P73;

the A/C (rs2279115) AA genotype in the gene encoding BCL2;

the +3100 A/G (rs2317676) AG or GG genotype in the gene encoding ITGB3;

the C/Del (rs1799732) CDel or DelDel genotype in the gene encoding DRD2;

or

the C/T (rs763110) TT genotype in the gene encoding Fas ligand;

is indicative of a reduced risk of developing lung cancer.

20. A method according to claim 18 wherein a result indicating the presence of one or more of:

the Ser307Ser G/T GG or GT genotype in the gene encoding XRCC4;

the A/T c74delA AT or TT genotype in the gene encoding CYP3A43;

the −

3714 G/T (rs6413429) GT or TT genotype in the gene encoding DAT 1;

the A/G (rs1139417) AA genotype in the gene encoding TNFR1;

or

the C/T (rs5743836) CC genotype in the gene encoding TLR9;

is indicative of an increased risk of developing lung cancer.

21. The method according to any one of claims 18 to 20 additionally comprising analysing the result for the presence or absence of one or more further polymorphisms selected from the group consisting of:

R19W A/G in the gene encoding Cerberus 1 (Cer

     1);

K3326X A/T in the breast cancer 2 early onset gene (BRCA2);

V433M A/G in the gene encoding Integrin alpha-1;

E375G T/C in the gene encoding Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1);

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding Tumor protein P73 (P73);

or one or more polymorphisms which are in linkage disequilibrium with any or more of these polymorphisms.

22. A method according to any one of claims 18 to 21 comprising analysing the result for the presence or absence of each of the polymorphisms selected from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

23. A method according to any one of claims 18 to 21 comprising analysing the result for the presence or absence of each of the polymorphisms selected from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs

     1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

24. A method according to any one of claims 18 to 21 comprising analysing the result for the presence or absence of each of the polymorphisms selected from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs

     1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

V433M A/G (rs2306022) in the gene encoding ITGA11;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

25. A method according to any one of claims 18 to 21 comprising analysing the result for the presence or absence of each of the polymorphisms selected from the group consisting of:

Rsa 1 C/T (rs2031920) in the gene encoding CYP 2E1;

G/C (rs360721) in the promoter of the gene encoding lnterleukin-18;

-251 A/T (rs4073) in the gene encoding Interleukin-8;

−

511 A/G (rs

     16944) in the gene encoding Interleukin 1B;

V433M A/G (rs2306022) in the gene encoding ITGA11;

Arg 197 Gln A/G (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

R19W A/G (rs

     10115703) in the gene encoding Cerberus 1;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

A/G (rs1139417) in the gene encoding TNFR1;

C/T (rs5743836) in the gene encoding TLR9;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs

     1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

−

751 G/T (rs

     13181) in the promoter of the gene encoding XPD;

Phe 257 Ser C/T (rs3087386) in the gene encoding REV1;

C/T (rs763110) in the gene encoding FasL;

29. The use of one or more polymorphisms selected from the group consisting of:

Ser307Ser G/T polymorphism in the X-ray repair complementing defective repair in Chinese hamster cells 4 gene (XRCC4);

A/T c74delA in the gene encoding cytochrome P450 polypeptide CYP3A43;

A/C (rs2279115) in the gene encoding B-cell CLL/lymphoma 2;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding Integrin beta 3;

−

3714 G/T (rs6413429) in the gene encoding Dopamine transporter 1;

A/G (rs

     1139417) in the gene encoding Tumor necrosis factor receptor 1;

C/Del (rs1799732) in the gene encoding Dopamine receptor D2;

C/T (rs763110) in the gene encoding Fas ligand;

C/T (rs5743836) in the gene encoding Toll-like receptor 9;

or one or more polymorphisms in linkage disequilibrium with one or more of these polymorphisms in the assessment of a subject'"'"'s risk of developing lung cancer.

30. The use according to claim 29, wherein said use is in conjunction with the use of at least one further polymorphism selected from the group consisting of:

R19W A/G in the gene encoding Cerberus 1 (Cer

     1);

K3326X A/T in the breast cancer 2 early onset gene (BRCA2);

V433M A/G in the gene encoding Integrin alpha-1;

E375G T/C in the gene encoding Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1);

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding Tumor protein P73 (P73);

or one or more polymorphisms in linkage disequilibrium with any one of said polymorphisms.

31. The use according to claim 29 or 30 wherein said use is of each of the polymorpyisms selected from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

32. The use according to claim 29 or 30 wherein said use is of each of the polymorpyisms selected from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

33. The use according to claim 29 or 30 wherein said use is of each of the polymorpyisms selected from the group consisting of:

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

Arg 197 Gln (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

V433M A/G (rs2306022) in the gene encoding ITGA11;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

34. The use according to claim 29 or 30 wherein said use is of each of the polymorpyisms selected from the group consisting of:

Rsa 1 C/T (rs2031920) in the gene encoding CYP 2E1;

−

133 G/C (rs360721) in the promoter of the gene encoding Interleukin-18;

−

251 A/T (rs4073) in the gene encoding Interleukin-8;

−

511 A/G (rs

     16944) in the gene encoding Interleukin 1B;

V433M A/G (rs2306022) in the gene encoding ITGA11;

Arg 197 Gln A/G (rs

     1799930) in the gene encoding N-acetylcysteine transferase 2;

Ala 15 Thr A/G (rs4934) in the gene encoding α

1-antichymotrypsin;

R19W A/G (rs

     10115703) in the gene encoding Cerberus 1;

−

3714 G/T (rs6413429) in the gene encoding DAT 1;

A/G (rs1139417) in the gene encoding TNFR1;

C/T (rs5743836) in the gene encoding TLR9;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding P73;

Arg 312 Gln (rs

     1799895) in the gene encoding SOD3;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding ITGB3;

C/Del (rs1799732) in the gene encoding DRD2;

A/C (rs2279115) in the gene encoding BCL2;

−

751 G/T (rs

     13181) in the promoter of the gene encoding XPD;

Phe 257 Ser C/T (rs3087386) in the gene encoding REV1;

C/T (rs763110) in the gene encoding FasL;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

37. A method of determining a subject'"'"'s risk of developing lung cancer, comprising the analysis of two or more polymorphisms selected from the group consisting of:

Ser307Ser G/T in the X-ray repair complementing defective repair in Chinese hamster cells 4 gene (XRCC4)

R19W A/G in the gene encoding Cerberus 1 (Cer

     1);

K3326X A/T in the breast cancer 2 early onset gene (BRCA2);

V433M A/G in the gene encoding Integrin alpha-11;

or

E375G T/C in the gene encoding Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1);

A/T c74delA in the gene encoding cytochrome P450 polypeptide CYP3A43;

A/C (rs2279115) in the gene encoding B-cell CLL/lymphoma 2;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding Integrin beta 3;

−

3714 G/T (rs6413429) in the gene encoding Dopamine transporter 1;

A/G (rs1139417) in the gene encoding Tumor necrosis factor receptor 1;

C/Del (rs1799732) in the gene encoding Dopamine receptor D2;

C/T (rs763110) in the gene encoding Fas ligand;

C/T (rs5743836) in the gene encoding Toll-like receptor 9;

−

81 C/T (rs

     2273953) in the 5′

UTR of the gene encoding Tumor protein P73;

or one or more polymorphisms in linkage disequilibrium with any one or more of these polymorphisms.

52. A method of assessing a subject'"'"'s suitability for an intervention diagnostic of or therapeutic for lung cancer, the method comprising:

a) providing a net score for said subject, wherein the net score is or has been determined by;

i) providing the result of one or more genetic tests of a sample from the subject, and analysing the result for the presence or absence of protective polymorphisms and for the presence or absence of susceptibility polymorphisms, wherein said protective and susceptibility polymorphisms are associated with lung cancer,

ii) assigning a positive score for each protective polymorphism and a negative score for each susceptibility polymorphism or vice versa;

iii) calculating a net score for said subject by representing the balance between the combined value of the protective polymorphisms and the combined value of the susceptibility polymorphisms present in the subject sample; and

b) providing a distribution of net scores for lung cancer sufferers and non-sufferers wherein the net scores for lung cancer sufferers and non-sufferers are or have been determined in the same manner as the net score determined for said subject; and

c) determining whether the net score for said subject lies within a threshold on said distribution separating individuals deemed suitable for said intervention from those for whom said intervention is deemed unsuitable;

wherein a net score within said threshold is indicative of the subject'"'"'s suitability for the intervention, and wherein a net score outside the threshold is indicative of the subject'"'"'s unsuitability for the intervention.

53. The method according to claim 52 wherein the value assigned to each protective polymorphism is the same.

54. The method according to any one of claims 52 to 53 wherein the value assigned to each susceptibility polymorphism is the same.

55. The method according any one of claims 52 to 54 wherein the intervention is a diagnostic test for lung cancer.

56. The method according to any one of claims 52 to 54 wherein intervention is a therapeutic intervention for lung cancer.

57. The method according to claim 52 wherein the lung cancer is selected from the group consisting of non-small cell lung cancer including adenocarcinoma and squamous cell carcinoma, small cell lung cancer, carcinoid tumor, lymphoma, or metastatic cancer.

58. The method according to claim 52 wherein the protective and susceptibility polymorphisms are selected from the group consisting of:

the −

133 G/C polymorphism in the Interleukin-18 gene;

the −

1053 C/T polymorphism in the CYP 2E1 gene;

the Arg197gln polymorphism in the Nat2 gene;

the −

511 G/A polymorphism in the Interleukin IB gene;

the Ala 9 Thr polymorphism in the Anti-chymotrypsin gene;

the S allele polymorphism in the Alpha1-antitrypsin gene;

the −

251 A/T polymorphism in the Interleukin-8 gene;

the Lys 751 gln polymorphism in the XPD gene;

the +760 G/C polymorphism in the SOD3 gene;

the Phe257Ser polymorphism in the REV gene;

the Z alelle polymorphism in the Alpha1-antitrypsin gene;

the R19W A/G polymorphism in the Cerberus 1 (Cer

     1) gene;

the Ser307Ser G/T polymorphism in the XRCC4 gene;

the K3326X A/T polymorphism in the BRCA2 gene;

the V433M A/G polymorphism in the Integrin alpha-11 gene;

the E375G T/C polymorphism in the CAMKK1 gene;

the A/T c74delA polymorphism in the gene encoding cytochrome P450 polypeptide CYP3A43;

the A/C (rs2279115) polymorphism in the gene encoding B-cell CLL/lymphoma 2;

the A/G at +3100 in the 3′

UTR (rs2317676) polymorphism of the gene encoding Integrin beta 3;

the −

3714 G/T (rs6413429) polymorphism in the gene encoding Dopamine transporter 1;

the A/G (rs1139417) polymorphism in the gene encoding Tumor necrosis factor receptor 1;

the C/Del (rs1799732) polymorphism in the gene encoding Dopamine receptor D2;

the C/T (rs763110) polymorphism in the gene encoding Fas ligand;

the C/T (rs5743836) polymorphism in the gene encoding Toll-like receptor 9;

the −

81 C/T (rs

     2273953) polymorphism in the 5′

UTR of the gene encoding Tumor protein P73;

or one or more polymorphisms in linkage disequilibrium with one or more of said polymorphisms.

63. The method according to claim 57 or 58 wherein said intervention is a CT scan for lung cancer.

64. The method according to any one of claims 52 to 58 as described herein with reference to the examples and/or figures.

65. A kit for assessing a subject'"'"'s risk of developing one or more obstructive lung diseases selected from lung cancer, said kit comprising a means of analysing a sample from said subject for the presence or absence of one or more polymorphisms selected from the group consisting of:

Ser307Ser G/T polymorphism in the X-ray repair complementing defective repair in Chinese hamster cells 4 gene (XRCC4);

A/T c74delA in the gene encoding cytochrome P450 polypeptide CYP3A43;

A/C (rs2279115) in the gene encoding B-cell CLL/lymphoma 2;

A/G at +3100 in the 3′

UTR (rs2317676) of the gene encoding Integrin beta 3;

−

3714 G/T (rs6413429) in the gene encoding Dopamine transporter 1;

A/G (rs

     1139417) in the gene encoding Tumor necrosis factor receptor 1;

C/Del (rs1799732) in the gene encoding Dopamine receptor D2;

C/T (rs763110) in the gene encoding Fas ligand;

C/T (rs5743836) in the gene encoding Toll-like receptor 9;

or one or more polymorphisms which are in linkage disequilibrium with one or more of these polymorphisms.