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1. WO2020109820 - MOLECULAR SIGNATURE

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

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CLAIMS

1. A method of identifying whether or not an individual has a pre-invasive lung lesion that will progress to an invasive lung cancer, the method comprising:

(a) providing a sample of nucleic acid which has been taken from a tissue of the individual, wherein the tissue is suspected of harbouring a pre-invasive lung lesion;

(b) performing an assay to determine a progression score for the sample; and

(c) identifying whether or not the individual has a pre-invasive lung lesion that will progress to an invasive lung cancer by comparing the progression score to a threshold value;

wherein the progression score is determined using a molecular signature selected from:

i) a differentially expressed gene (DEG) signature; ii) a differentially methylated position (DMP) signature;

iii) a copy number variation (CNV) signature; and

iv) combinations of (i) to (iii).

2. The method of claim 1, wherein:

the individual is identified as having a pre-invasive lung lesion that will progress to an invasive lung cancer if the progression score determined for the sample is higher than the threshold value; or

the individual is identified as not having a pre-invasive lung lesion that will progress to an invasive lung cancer if the progression score determined for the sample is lower than the threshold value.

3. The method of claim 1 or 2, wherein the DEG signature comprises the expression level of each of at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 75, at least 100, at least 150, at least 200, at least 250, at least 300, at least 325, least 350, at least 375, or 397 genes identified in Table 1, optionally wherein the method achieves an ROC AUC of at least 0.6, at least 0.60, at least 0.61, at least

0.62, at least 0.63, at least 0.64, at least 0.65, at least 0.66, at least 0.67, at least 0.68, at least 0.69, at least 0.7, at least 0.70, at least 0.71, at least 0.72, at least 0.73, at least 0.74, at least 0.75, at least 0.76, at least 0.77, at least 0.78, at least 0.79, at least 0.8, at least 0.80, at least 0.81, at least 0.82, at least 0.83, at least 0.84, at least 0.85, at least 0.86, or at least 0.87, optionally wherein the method achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %.

4. The method of claim 3, wherein the threshold value is from about 0.02 to about 0.6.

5. The method of any one of claims 1-4, wherein the DEG signature comprises the expression level of each of the genes identified in:

(i) Table 5, optionally wherein the threshold value is about 0.3, preferably wherein the method also achieves an ROC AUC of at least about 0.6 or about 0.64 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %;

(ii) Table 4, optionally wherein the threshold value is about 0.035, preferably wherein the method also achieves an ROC AUC of at least about 0.65 or about 0.69 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %;

(iii) Table 3, optionally wherein the threshold value is about 0.04, preferably wherein the method also achieves an ROC AUC of at least about 0.7 or about 0.76 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %;

(iv) Table 2, optionally wherein the threshold value is about 0.105, preferably wherein the method also achieves an ROC AUC of at least about 0.75 or about 0.81 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %; or

(v) Table 1, optionally wherein the threshold value is about 0.14, preferably wherein the method achieves an ROC AUC of at least about 0.85 or about 0.87,

optionally wherein the method achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %.

6. The method of any one of claims 1-5, wherein the DMP signature comprises the methylation status (b) of least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, at least 12, least 14, at least 16, at least 18, at least 20, at least 25, at least 50, at least 75, at least 100, at least 125, or differentially methylated positions (DMPs) selected from Table 11, optionally wherein the method achieves an ROC AUC of at least 0.9, at least 0.90, at least 0.91, at least 0.92, at least 0.93, at least 0.94, at least 0.95, at least 0.96, at least 0.97, at least 0.98, or at least 0.99, optionally wherein the method achieves a sensitivity of at least about 95 % and/or a specificity of at least about 50 %.

7. The method of claim 6, wherein the threshold value is from about 0.3 to about

0.6.

8. The method of any one of claims 1-7, wherein the DMP signature comprises the b of each of the DMPs identified in:

(i) Table 16 or Table 17, optionally wherein the threshold value is about 0.43 or about 0.44, preferably wherein the method achieves an ROC AUC of at least about 0.9 or about 0.94 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 60 %;

(ii) Table 15, optionally wherein the threshold value is about 0.45, preferably wherein the method achieves an ROC AUC of at least about 0.93 or about 0.96 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 50 %;

(iii) Table 14, optionally wherein the threshold value is about 0.45, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.99 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %;

(iv) Table 13, optionally wherein the threshold value is about 0.46, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.996 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %;

(v) Table 12, optionally wherein the threshold value is about 0.48, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.999 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %; or

(vi) Table 11, optionally wherein the threshold value is about 0.5, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.998 and or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 55 %.

9. The method of any one of claims 1-8, wherein the CNV signature comprises the amplification or loss of at least 5, at least 6, least 7, at least 8, at least 9, at least 10, at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, or at least 200 CNV bands identified in Table 19, optionally wherein the method achieves an ROC AUC of at least about 0.9, at least about 0.91, at least about 0.92, at least about 0.93, at least about 0.94, at least about 0.95, at least about 0.96, at least about 0.97, at least about 0.98, at least about 0.99, optionally wherein the method achieves a sensitivity of at least about 75 %, at least about 80 %, at least about 85 %, at least about 90 %, or at least about 95 %, and/or a specificity of at least about 65 %, at least about 70 %, at least about 75 %, at least about 80 %, at least about 85 %, at least about 90 %, or at least about 95 %.

10. The method of claim 9, wherein the threshold value is from about 0.05 to about

0.6.

11. The method of any one of claims 1-10, wherein the CNV signature comprises the amplification or loss of the CNV bands identified in:

(i) Table 34, optionally wherein the threshold value is about 0.66, preferably wherein the method achieves an ROC AUC of at least about 0.9 or about 0.95 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 65 %;

(ii) Table 33, optionally wherein the threshold value is about 0.65, preferably wherein the method achieves an ROC AUC of at least about 0.9 or about 0.95 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 70 %;

(iii) Table 32, optionally wherein the threshold value is about 0.6, preferably wherein the method achieves an ROC AUC of at least about 0.9 or about 0.95 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 85 %;

(iv) Table 31, optionally wherein the threshold value is about 0.56, preferably wherein the method achieves an ROC AUC of at least about 0.9 or about 0.96 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 85 %;

(v) Table 30, optionally wherein the threshold value is about 0.48, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.96 and/or achieves a sensitivity of at least about 90 % and/or a specificity of at least about 90 %;

(vi) Table 29, optionally wherein the threshold value is about 0.41, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.96 and/or achieves a sensitivity of at least about 90 % and/or a specificity of at least about 90 %;

(vii) Table 28, optionally wherein the threshold value is about 0.31, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.97 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 90 %;

(viii) Table 27, optionally wherein the threshold value is about 0.19, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.97 and/or achieves a sensitivity of at least about 80 % and/or a specificity of at least about 95 %;

(ix) Table 26, optionally wherein the threshold value is about 0.12, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.97 and/or achieves a sensitivity of at least about 90 % and/or a specificity of at least about 95 %;

(x) Table 25, optionally wherein the threshold value is about 0.06, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.98 and/or achieves a sensitivity of at least about 90 % and/or a specificity of at least about 95 %;

(xi) Table 24, optionally wherein the threshold value is about 0.02, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.98 and/or achieves a sensitivity of at least about 90 % and/or a specificity of at least about 95 %;

(xii) Table 23, optionally wherein the threshold value is about 0.01, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.98 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 95 %; (xiii) Table 22, optionally wherein the threshold value is about 0.01, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.98 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 90 %;

(xiv) Table 21, optionally wherein the threshold value is about 0.02, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.98 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 90 %;

(xv) Table 20, optionally wherein the threshold value is about 0.01, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.98 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 90 %; or

(xvi) Table 19, optionally wherein the threshold value is about 0.02, preferably wherein the method achieves an ROC AUC of at least about 0.95 or about 0.98 and/or achieves a sensitivity of at least about 95 % and/or a specificity of at least about 85 %.

12. A method of treating a pre-invasive lung lesion and/or treating and/or preventing an invasive lung cancer in an individual comprising:

identifying a pre-invasive lung lesion in an individual that will progress to an invasive lung cancer by performing a method according to any one of claims 1-1 1; and administering a lung cancer therapy to the individual, optionally wherein the therapy comprises surgical intervention.

13. The method of any one of claims 1-12, wherein the sample is from an individual who:

(g) is not suspected of having cancer;

(h) is suspected of having a pre-invasive lung lesion but not suspected of having cancer;

(i) has a pre-invasive lung lesion but is not suspected of having cancer;

(j) has a pre-invasive lung lesion and is suspected of having cancer;

(k) is suspected of having cancer; or

(l) has cancer.

14. The method of any one of claims 1-13, wherein the tissue from which the nucleic acid sample has been taken:

(i) has been obtained from a biopsy;

(iii) is processed by laser-capture micro-dissection (LCM); and/or

(ii) is fresh-frozen tissue or formal in- fixed paraffin-embedded (FFPE) tissue.

15. The method of any one claims 1 -14, wherein the nucleic acid is a DNA.

16. The method of any one of claims 1-15, wherein the progression score is determined using a DEG signature and the assay in step (b) comprises performing a hybrisation assay.

17. The method of claims 15 or 16, wherein the progression score is determined using a DMP signature and the assay in step (b) comprises bisulphite conversion of the DNA, optionally wherein step (b) comprises performing a sequencing step to determine the sequence of the DNA molecules, optionally wherein before sequencing an amplification step is performed; and/or optionally wherein step (b) comprises

(i) hybridising the DNA to an array comprising probes capable of discriminating between methylated and non- methylated forms of DNA and applying a detection system to the array to discriminate methylated and non-methylated forms of DNA, optionally wherein before hybridisation an amplification step is performed; or

(ii) performing an amplification step using methylation-specific primers, wherein the methylation status of the DNA is determined by the presence or absence of an amplified product, optionally wherein the amplification step is performed by PCR.

18. The method of any one of claims 15-17, wherein the progression score is determined using a CNV signature and the assay in step (b) comprises whole genome sequencing.

19. The method of any one of claims 1-14, wherein the nucleic acid is an RNA.

20. The method of claim 19, wherein the progression score is determined using a DEG signature and the assay in step (b) comprises RT-qPCR.

21. A molecular signature as defined in any one of claims 1-20 for identifying whether or not an individual has a pre-invasive lung lesion that will progress to an invasive lung cancer.

22. Use of a molecular signature as defined in any one of claims 1 -21 for identifying whether or not an individual has a pre-invasive lung lesion that will progress to an invasive lung cancer, optionally wherein the use of the molecular signature is in an ex-vivo method for identifying whether or not an individual has a pre-invasive lung lesion that will progress to an invasive lung cancer.

23. The method of any one of claims 1 -20, the molecular signature of claim 21 , or the use according to claim 22, wherein pre-invasive lung lesion is a solid lesion and/or the invasive lung cancer is a solid tumour.

24. The method, molecular signature or use according to any one of claims 1 -23, wherein the pre-invasive lung lesion is normal epithelium, tissue hyperplasia, dysplasia, or lung carcinoma in situ (CIS).

25. The method, molecular signature or use according to any one of claims 1 -24, wherein the lung cancer is lung squamous cell carcinoma (LUSC).