US2020239967A1PendingUtilityA1
Method of diagnosis, staging and monitoring of melanoma using microrna gene expression
Est. expiryOct 3, 2037(~11.2 yrs left)· nominal 20-yr term from priority
Inventors:Ryan Van Laar
C12Q 2600/158C12Q 2600/112C12Q 2600/178C12Q 1/6886G01N 2800/7028G16B 25/10G16B 40/00
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Claims
Abstract
The present invention relates to methods of diagnosing melanoma in a subject, the method comprising detecting microRNA expression levels. The present invention also relates to methods of assessing the disease stage of melanoma and/or monitoring said melanoma stage. Also, the present invention relates to selecting a treatment or modifying a treatment based on the diagnosis or stage of melanoma. Further the present invention relates to a system for detecting and diagnosing melanoma in a patient and for determining the disease stage of melanoma.
Claims
exact text as granted — not AI-modified1 . A method for detecting and diagnosing melanoma in a subject, comprising:
(i) detecting microRNA expression levels in a biological sample, (ii) calculating a classification score (CS) of the biological sample based on one or more algorithms derived from a dataset comprising the expression levels of said microRNAs, and (iii) classifying the biological sample as melanoma or not based on the value of the classification score
wherein the microRNA consist of:
hsa-let-7e-5p,
hsa-miR-3127-5p,
hsa-miR-105-5p,
hsa-miR-3131,
hsa-miR-1180-3p,
hsa-miR-331-3p,
hsa-miR-1258,
hsa-miR-337-5p,
hsa-miR-1264,
hsa-miR-34a-5p,
hsa-miR-1269a,
hsa-miR-3928-3p,
hsa-miR-127-5p,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-1306-5p,
hsa-miR-450a-5p,
hsa-miR-138-5p,
hsa-miR-4532,
hsa-miR-152-3p,
hsa-miR-454-3p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-497-5p,
hsa-miR-1-5p,
hsa-miR-520d-3p,
hsa-miR-181b-5p,
hsa-miR-521,
hsa-miR-1910-5p,
hsa-miR-522-3p,
hsa-miR-1973,
hsa-miR-548a-5p,
hsa-miR-199b-5p,
hsa-miR-548ad-3p,
hsa-miR-205-5p,
hsa-miR-548l,
hsa-miR-219a-2-3p,
hsa-miR-553,
hsa-miR-2682-5p,
hsa-miR-624-3p,
hsa-miR-27a-3p,
hsa-miR-652-3p,
hsa-miR-299-3p,
hsa-miR-660-5p,
hsa-miR-301a-3p,
hsa-miR-764
2 . The method according to claim 1 , wherein the microRNA consist of:
hsa-miR-1258,
hsa-miR-3131,
hsa-miR-1264,
hsa-miR-337-5p,
hsa-miR-1269a,
hsa-miR-34a-5p,
hsa-miR-1302,
hsa-miR-3928-3p,
hsa-miR-1306-5p,
hsa-miR-424-5p,
hsa-miR-138-5p,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-450a-5p,
hsa-miR-1537-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-1-5p,
hsa-miR-4787-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-520d-3p,
hsa-miR-1973,
hsa-miR-522-3p,
hsa-miR-205-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p,
hsa-miR-2682-5p,
hsa-miR-548l,
hsa-miR-27a-3p,
hsa-miR-553,
hsa-miR-299-3p,
hsa-miR-624-3p,
hsa-miR-301a-3p,
hsa-miR-764
3 . The method according to claim 1 or 2 , wherein the microRNA consist of:
hsa-miR-1258,
hsa-miR-34a-5p,
hsa-miR-1264,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p.
hsa-miR-299-3p,
4 . A method of determining the disease stage of melanoma said method comprising
(i) detecting microRNA expression levels in a biological sample, (ii) calculating a staging score (SS) of the biological sample based on a dataset comprising the expression levels of said microRNAs, and (iii) classifying the biological sample as a stage of melanoma based on the value of the staging score
wherein the microRNA consist of:
hsa-let-7e-5p,
hsa-miR-3127-5p.
hsa-miR-105-5p,
hsa-miR-3131,
hsa-miR-1180-3p,
hsa-miR-331-3p,
hsa-miR-1258,
hsa-miR-337-5p,
hsa-miR-1264,
hsa-miR-34a-5p,
hsa-miR-1269a,
hsa-miR-3928-3p,
hsa-miR-127-5p,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-1306-5p,
hsa-miR-450a-5p,
hsa-miR-138-5p,
hsa-miR-4532,
hsa-miR-152-3p,
hsa-miR-454-3p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-497-5p,
hsa-miR-1-5p,
hsa-miR-520d-3p,
hsa-miR-181b-5p,
hsa-miR-521,
hsa-miR-1910-5p,
hsa-miR-522-3p,
hsa-miR-1973,
hsa-miR-548a-5p,
hsa-miR-199b-5p,
hsa-miR-548ad-3p,
hsa-miR-205-5p,
hsa-miR-548l,
hsa-miR-219a-2-3p,
hsa-miR-553,
hsa-miR-2682-5p,
hsa-miR-624-3p,
hsa-miR-27a-3p,
hsa-miR-652-3p,
hsa-miR-299-3p,
hsa-miR-660-5p,
hsa-miR-301a-3p,
hsa-miR-764
5 . The method according to claim 4 wherein the microRNA consist of:
hsa-let-7e-5p,
hsa-miR-299-3p,
hsa-miR-105-5p,
hsa-miR-301a-3p,
hsa-miR-1180-3p,
hsa-miR-3127-5p
hsa-miR-127-5p,
hsa-miR-331-3p,
hsa-miR-152-3p,
hsa-miR-337-5p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-521,
hsa-miR-199b-5p,
hsa-miR-652-3p,
hsa-miR-27a-3p,
hsa-miR-660-5p
6 . The method according to claim 4 , wherein the staging of the melanoma is stage I or II or III or IV.
7 . A method for monitoring melanoma in a subject, wherein the level of expression of miRNA is detected in a biological sample, wherein the
microRNA consist of:
(a)
hsa-let-7e-5p,
hsa-miR-205-5p,
hsa-miR-105-5p,
hsa-miR-219a-2-3p,
hsa-miR-1180-3p,
hsa-miR-2682-5p,
hsa-miR-1258,
hsa-miR-27a-3p,
hsa-miR-1264,
hsa-miR-299-3p,
hsa-miR-1269a,
hsa-miR-301a-3p,
hsa-miR-127-5p,
hsa-miR-3127-5p.
hsa-miR-1302,
hsa-miR-3131,
hsa-miR-1306-5p,
hsa-miR-331-3p,
hsa-miR-138-5p,
hsa-miR-337-5p,
hsa-miR-152-3p,
hsa-miR-34a-5p,
hsa-miR-1537-3p,
hsa-miR-3928-3p,
hsa-miR-154-5p,
hsa-miR-424-5p,
hsa-miR-1-5p,
hsa-miR-431-5p,
hsa-miR-181b-5p,
hsa-miR-450a-5p,
hsa-miR-1910-5p,
hsa-miR-4532,
hsa-miR-1973,
hsa-miR-454-3p,
hsa-miR-199b-5p,
hsa-miR-4787-3p,
hsa-miR-497-5p,
hsa-miR-548l,
hsa-miR-520d-3p,
hsa-miR-553,
hsa-miR-521,
hsa-miR-624-3p,
hsa-miR-522-3p,
hsa-miR-652-3p,
hsa-miR-548a-5p,
hsa-miR-660-5p,
hsa-miR-548ad-3p,
hsa-miR-764
or
(b)
hsa-miR-1258,
hsa-miR-3131,
hsa-miR-1264,
hsa-miR-337-5p,
hsa-miR-1269a,
hsa-miR-34a-5p,
hsa-miR-1302,
hsa-miR-3928-3p,
hsa-miR-1306-5p,
hsa-miR-424-5p,
hsa-miR-138-5p,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-450a-5p,
hsa-miR-1537-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-1-5p,
hsa-miR-4787-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-520d-3p,
hsa-miR-1973,
hsa-miR-522-3p,
hsa-miR-205-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p,
hsa-miR-2682-5p,
hsa-miR-548l,
hsa-miR-27a-3p,
hsa-miR-553,
hsa-miR-299-3p,
hsa-miR-624-3p,
hsa-miR-301a-3p,
hsa-miR-764
or
(c)
hsa-miR-1258,
hsa-miR-152-3p,
hsa-miR-1264,
hsa-miR-154-5p,
hsa-miR-1302,
hsa-miR-181b-5p,
hsa-miR-1910-5p,
hsa-miR-4532,
hsa-miR-219a-2-3p,
hsa-miR-454-3p,
hsa-miR-299-3p,
hsa-miR-497-5p,
hsa-miR-34a-5p,
hsa-miR-548a-5p,
hsa-miR-424-5p,
hsa-miR-548ad-3p
hsa-miR-431-5p,
8 . A method of monitoring the status of melanoma for relapse or recurrence in a subject previously diagnosed with melanoma, said method comprising
(i) detecting microRNA expression levels in a biological sample, (ii) calculating a classification score (CS) of the biological sample based on one or more algorithms from a dataset comprising the expression levels of said microRNAs, and (iii) classifying the biological sample as melanoma or not based on the value of the classification score and comparing to a previously determined classification threshold, which separates those with melanoma from those without
wherein microRNA consist of:
(a)
hsa-let-7e-5p,
hsa-miR-1910-5p,
hsa-miR-105-5p,
hsa-miR-1973,
hsa-miR-1180-3p,
hsa-miR-199b-5p,
hsa-miR-1258,
hsa-miR-205-5p,
hsa-miR-1264,
hsa-miR-219a-2-3p,
hsa-miR-1269a,
hsa-miR-2682-5p,
hsa-miR-127-5p,
hsa-miR-27a-3p,
hsa-miR-1302,
hsa-miR-299-3p,
hsa-miR-1306-5p,
hsa-miR-301a-3p,
hsa-miR-138-5p,
hsa-miR-3127-5p.
hsa-miR-152-3p,
hsa-miR-3131,
hsa-miR-1537-3p,
hsa-miR-331-3p,
hsa-miR-154-5p,
hsa-miR-337-5p,
hsa-miR-1-5p,
hsa-miR-34a-5p,
hsa-miR-181b-5p,
hsa-miR-3928-3p,
hsa-miR-424-5p,
hsa-miR-522-3p,
hsa-miR-431-5p,
hsa-miR-548a-5p,
hsa-miR-450a-5p,
hsa-miR-548ad-3p,
hsa-miR-4532,
hsa-miR-548l,
hsa-miR-454-3p,
hsa-miR-553,
hsa-miR-4787-3p,
hsa-miR-624-3p,
hsa-miR-497-5p,
hsa-miR-652-3p,
hsa-miR-520d-3p,
hsa-miR-660-5p,
hsa-miR-521,
hsa-miR-764
or
(b)
hsa-miR-1258,
hsa-miR-3131,
hsa-miR-1264,
hsa-miR-337-5p,
hsa-miR-1269a,
hsa-miR-34a-5p,
hsa-miR-1302,
hsa-miR-3928-3p,
hsa-miR-1306-5p,
hsa-miR-424-5p,
hsa-miR-138-5p,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-450a-5p,
hsa-miR-1537-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-1-5p,
hsa-miR-4787-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-520d-3p,
hsa-miR-1973,
hsa-miR-522-3p,
hsa-miR-205-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p,
hsa-miR-2682-5p,
hsa-miR-548l,
hsa-miR-27a-3p,
hsa-miR-553,
hsa-miR-299-3p,
hsa-miR-624-3p,
hsa-miR-301a-3p,
hsa-miR-764
or
(c)
hsa-miR-1258,
hsa-miR-34a-5p,
hsa-miR-1264,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p.
hsa-miR-152-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p
hsa-miR-299-3p,
9 . The method according to claim 8 , wherein the biological sample is solid tissue, plasma, blood, skin, exosomes, urine, milk, serum, ascites, cyst fluid, pleural fluid, peritoneal fluid, cerebral spinal fluid, tears, saliva, sputum, hair or combinations thereof.
10 . A method for treating melanoma in a subject comprising administering to said subject a therapeutically effective amount of an agent
wherein said agent modifies directly or indirectly the expression level of miRNA consisting of:
(a)
hsa-let-7e-5p,
hsa-miR-1-5p,
hsa-miR-105-5p,
hsa-miR-181b-5p,
hsa-miR-1180-3p,
hsa-miR-1910-5p,
hsa-miR-1258,
hsa-miR-1973,
hsa-miR-1264,
hsa-miR-199b-5p,
hsa-miR-1269a,
hsa-miR-205-5p,
hsa-miR-127-5p,
hsa-miR-219a-2-3p,
hsa-miR-1302,
hsa-miR-2682-5p,
hsa-miR-1306-5p,
hsa-miR-27a-3p,
hsa-miR-138-5p,
hsa-miR-299-3p,
hsa-miR-152-3p,
hsa-miR-301a-3p,
hsa-miR-1537-3p,
hsa-miR-3127-5p.
hsa-miR-154-5p,
hsa-miR-3131,
hsa-miR-331-3p,
hsa-miR-520d-3p,
hsa-miR-337-5p,
hsa-miR-521,
hsa-miR-34a-5p,
hsa-miR-522-3p,
hsa-miR-3928-3p,
hsa-miR-548a-5p,
hsa-miR-424-5p,
hsa-miR-548ad-3p,
hsa-miR-431-5p,
hsa-miR-548l,
hsa-miR-450a-5p,
hsa-miR-553,
hsa-miR-4532,
hsa-miR-624-3p,
hsa-miR-454-3p,
hsa-miR-652-3p,
hsa-miR-4787-3p,
hsa-miR-660-5p,
hsa-miR-497-5p,
hsa-miR-764
or
(b)
hsa-miR-1258,
hsa-miR-3131,
hsa-miR-1264,
hsa-miR-337-5p,
hsa-miR-1269a,
hsa-miR-34a-5p,
hsa-miR-1302,
hsa-miR-3928-3p,
hsa-miR-1306-5p,
hsa-miR-424-5p,
hsa-miR-138-5p,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-450a-5p,
hsa-miR-1537-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-1-5p,
hsa-miR-4787-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-520d-3p,
hsa-miR-1973,
hsa-miR-522-3p,
hsa-miR-205-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p,
hsa-miR-2682-5p,
hsa-miR-548l,
hsa-miR-27a-3p,
hsa-miR-553,
hsa-miR-299-3p,
hsa-miR-624-3p,
hsa-miR-301a-3p,
hsa-miR-764
or
(c)
hsa-let-7e-5p,
hsa-miR-299-3p,
hsa-miR-105-5p,
hsa-miR-301a-3p,
hsa-miR-1180-3p,
hsa-miR-3127-5p,
hsa-miR-127-5p,
hsa-miR-331-3p,
hsa-miR-152-3p,
hsa-miR-337-5p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-521,
hsa-miR-199b-5p,
hsa-miR-652-3p,
hsa-miR-27a-3p,
hsa-miR-660-5p
or
(d)
hsa-miR-1258,
hsa-miR-34a-5p,
hsa-miR-1264,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p
hsa-miR-299-3p,
11 . A method of selecting a treatment or modifying a treatment following an adverse melanoma outcome based on the expression levels of microRNA determined by a classification score,
said method comprising administering an agent effective in the treatment of melanoma which modifies directly or indirectly the expression level of miRNA consisting of:
(a)
hsa-let-7e-5p,
hsa-miR-3127-5p,
hsa-miR-105-5p,
hsa-miR-3131,
hsa-miR-1180-3p,
hsa-miR-331-3p,
hsa-miR-1258,
hsa-miR-337-5p,
hsa-miR-1264,
hsa-miR-34a-5p,
hsa-miR-1269a,
hsa-miR-3928-3p,
hsa-miR-127-5p,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-1306-5p,
hsa-miR-450a-5p,
hsa-miR-138-5p,
hsa-miR-4532,
hsa-miR-152-3p,
hsa-miR-454-3p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-497-5p,
hsa-miR-1-5p,
hsa-miR-520d-3p,
hsa-miR-181b-5p,
hsa-miR-521,
hsa-miR-1910-5p,
hsa-miR-522-3p,
hsa-miR-1973,
hsa-miR-548a-5p,
hsa-miR-199b-5p,
hsa-miR-548ad-3p,
hsa-miR-205-5p,
hsa-miR-548l,
hsa-miR-219a-2-3p,
hsa-miR-553,
hsa-miR-2682-5p,
hsa-miR-624-3p,
hsa-miR-27a-3p,
hsa-miR-652-3p,
hsa-miR-299-3p,
hsa-miR-660-5p,
hsa-miR-301a-3p,
hsa-miR-764;
or
(b)
hsa-miR-1258,
hsa-miR-3131,
hsa-miR-1264,
hsa-miR-337-5p,
hsa-miR-1269a,
hsa-miR-34a-5p,
hsa-miR-1302,
hsa-miR-3928-3p,
hsa-miR-1306-5p,
hsa-miR-424-5p,
hsa-miR-138-5p,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-450a-5p,
hsa-miR-1537-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-1-5p,
hsa-miR-4787-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-520d-3p,
hsa-miR-1973,
hsa-miR-522-3p,
hsa-miR-205-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p,
hsa-miR-2682-5p,
hsa-miR-548l,
hsa-miR-27a-3p,
hsa-miR-553,
hsa-miR-299-3p,
hsa-miR-624-3p,
hsa-miR-301a-3p,
hsa-miR-764
or
(c)
hsa-miR-1258,
hsa-miR-34a-5p,
hsa-miR-1264,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p
hsa-miR-299-3p,
12 . (canceled)
13 . The method according to claim 1 wherein said ageng is selected from one or more of the following:
(i) Immunotherapy, including: Aldesleukin (IL-2), Intron A (Recombinant Interferon Alfa-2b), Ipilimumab, Keytruda (Pembrolizumab), Pembrolizumab, Sylatron (Peginterferon Alfa-2b), Yervoy (Ipilimumab), Zelboraf (Vemurafenib),
(ii) Targeted/small-molecule therapy, including: Cobimetinib, Dabrafenib, Mekinist (Trametinib), Nivolumab (Opdivo), Vemurafenib
(iii) Chemotherapy, including: Dacarbazine
(iv) Viral therapy, including: Imlygic (Talimogene Laherparepvec)
(v) siRNA
(vi) antisense nucleic acids,
(vii) antagonist microRNAs: including, antagomirs,
(viii) enzymatic RNA molecules: including, ribozymes
(ix) miRNA agonist; and/or
(x) anti-miRNA antibodies
14 . (canceled)
15 . A molecular array or a series of reagents, comprising a plurality of:
(i) nucleic acid molecules comprising a nucleotide sequence corresponding to any one or more of the microRNA listed in Table 1 or a sequence exhibiting at least 80% identity thereto or a functional derivative, fragment, variant or homologue of said nucleic acid molecule; or (ii) nucleic acid molecules comprising a nucleotide sequence capable of binding to any one or more of the sequences of (i) under medium stringency conditions or a functional derivative, fragment, variant or homologue of said nucleic acid molecule; or (iii) nucleic acid probes or oligonucleotides comprising a nucleotide sequence capable of hybridising to any one or more of the sequences of (i) under medium stringency conditions or a functional derivative, fragment, variant or homologue of said nucleic acid molecule;
wherein the level of expression of said microRNA of (i)-(iii) is used to calculate a classification score (CS) which is indicative of the presence or absence of melanoma in a subject or a staging score (SS) which is indicative of the stage of melanoma in a subject.
16 . The molecular array according to claim 15 , wherein said miRNA consist of:
(a)
hsa-let-7e-5p,
hsa-miR-1973,
hsa-miR-105-5p,
hsa-miR-199b-5p,
hsa-miR-1180-3p,
hsa-miR-205-5p,
hsa-miR-1258,
hsa-miR-219a-2-3p,
hsa-miR-1264,
hsa-miR-2682-5p,
hsa-miR-1269a,
hsa-miR-27a-3p,
hsa-miR-127-5p,
hsa-miR-299-3p,
hsa-miR-1302,
hsa-miR-301a-3p,
hsa-miR-1306-5p,
hsa-miR-3127-5p.
hsa-miR-138-5p,
hsa-miR-3131,
hsa-miR-152-3p,
hsa-miR-331-3p,
hsa-miR-1537-3p,
hsa-miR-337-5p,
hsa-miR-154-5p,
hsa-miR-34a-5p,
hsa-miR-1-5p,
hsa-miR-3928-3p,
hsa-miR-181b-5p,
hsa-miR-424-5p,
hsa-miR-1910-5p,
hsa-miR-431-5p,
hsa-miR-450a-5p,
hsa-miR-548a-5p,
hsa-miR-4532,
hsa-miR-548ad-3p,
hsa-miR-454-3p,
hsa-miR-548l,
hsa-miR-4787-3p,
hsa-miR-553,
hsa-miR-497-5p,
hsa-miR-624-3p,
hsa-miR-520d-3p,
hsa-miR-652-3p,
hsa-miR-521,
hsa-miR-660-5p,
hsa-miR-522-3p,
hsa-miR-764;
or
(b)
hsa-miR-1258,
hsa-miR-3131,
hsa-miR-1264,
hsa-miR-337-5p,
hsa-miR-1269a,
hsa-miR-34a-5p,
hsa-miR-1302,
hsa-miR-3928-3p,
hsa-miR-1306-5p,
hsa-miR-424-5p,
hsa-miR-138-5p,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-450a-5p,
hsa-miR-1537-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-1-5p,
hsa-miR-4787-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-520d-3p,
hsa-miR-1973,
hsa-miR-522-3p,
hsa-miR-205-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p,
hsa-miR-2682-5p,
hsa-miR-548l,
hsa-miR-27a-3p,
hsa-miR-553,
hsa-miR-299-3p,
hsa-miR-624-3p,
hsa-miR-301a-3p,
hsa-miR-764
or
(c)
hsa-let-7e-5p,
hsa-miR-299-3p,
hsa-miR-105-5p,
hsa-miR-301a-3p,
hsa-miR-1180-3p,
hsa-miR-3127-5p,
hsa-miR-127-5p,
hsa-miR-331-3p,
hsa-miR-152-3p,
hsa-miR-337-5p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-521,
hsa-miR-199b-5p,
hsa-miR-652-3p,
hsa-miR-27a-3p,
hsa-miR-660-5p
or
(d)
hsa-miR-1258,
hsa-miR-34a-5p,
hsa-miR-1264,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p
hsa-miR-299-3p,
17 . A diagnostic kit for the diagnosis of a melanoma, assessment of disease stage of melanoma or assessment of disease susceptibility to a proposed treatment comprising:
a. at least one “forward” amplification primer; and/or b. at least one “reverse” amplification primer; and/or c. detection or capture probes for the microRNA
wherein the primers enable specific amplification of the nucleotide sequences of at least one microRNA selected from Table 1.
18 . The diagnostic kit according to claim 17 , wherein said miRNA consist of:
(a)
hsa-let-7e-5p,
hsa-miR-3127-5p,
hsa-miR-105-5p,
hsa-miR-3131,
hsa-miR-1180-3p,
hsa-miR-331-3p,
hsa-miR-1258,
hsa-miR-337-5p,
hsa-miR-1264,
hsa-miR-34a-5p,
hsa-miR-1269a,
hsa-miR-3928-3p,
hsa-miR-127-5p,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-1306-5p,
hsa-miR-450a-5p,
hsa-miR-138-5p,
hsa-miR-4532,
hsa-miR-152-3p,
hsa-miR-454-3p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-497-5p,
hsa-miR-1-5p,
hsa-miR-520d-3p,
hsa-miR-181b-5p,
hsa-miR-521,
hsa-miR-1910-5p,
hsa-miR-522-3p,
hsa-miR-1973,
hsa-miR-548a-5p,
hsa-miR-199b-5p,
hsa-miR-548ad-3p,
hsa-miR-205-5p,
hsa-miR-548l,
hsa-miR-219a-2-3p,
hsa-miR-553,
hsa-miR-2682-5p,
hsa-miR-624-3p,
hsa-miR-27a-3p,
hsa-miR-652-3p,
hsa-miR-299-3p,
hsa-miR-660-5p,
hsa-miR-301a-3p,
hsa-miR-764;
or
(b)
hsa-miR-1258,
hsa-miR-3131,
hsa-miR-1264,
hsa-miR-337-5p,
hsa-miR-1269a,
hsa-miR-34a-5p,
hsa-miR-1302,
hsa-miR-3928-3p,
hsa-miR-1306-5p,
hsa-miR-424-5p,
hsa-miR-138-5p,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-450a-5p,
hsa-miR-1537-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-1-5p,
hsa-miR-4787-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-520d-3p,
hsa-miR-1973,
hsa-miR-522-3p,
hsa-miR-205-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p,
hsa-miR-2682-5p,
hsa-miR-548l,
hsa-miR-27a-3p,
hsa-miR-553,
hsa-miR-299-3p,
hsa-miR-624-3p,
hsa-miR-301a-3p,
hsa-miR-764
or
(c)
hsa-let-7e-5p,
hsa-miR-299-3p,
hsa-miR-105-5p,
hsa-miR-301a-3p,
hsa-miR-1180-3p,
hsa-miR-3127-5p,
hsa-miR-127-5p,
hsa-miR-331-3p,
hsa-miR-152-3p,
hsa-miR-337-5p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-521,
hsa-miR-199b-5p,
hsa-miR-652-3p,
hsa-miR-27a-3p,
hsa-miR-660-5p
or
(d)
hsa-miR-1258,
hsa-miR-34a-5p,
hsa-miR-1264,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p
hsa-miR-299-3p,
19 . A system for detecting and diagnosing melanoma in a patient,
at least one processor; and at least one storage medium containing program instructions for execution by said processor, said program instructions causing said processor to execute steps comprising: (i) detecting microRNA expression levels in a biological sample from the patient, (ii) calculating a classification score (CS) of the biological sample based on one or more algorithms derived from a dataset comprising the expression levels of said microRNAs, and (iii) classifying the biological sample as melanoma or not based on the value of the classification score; wherein the miRNA consist of:
(a)
hsa-let-7e-5p,
hsa-miR-1302,
hsa-miR-105-5p,
hsa-miR-1306-5p,
hsa-miR-1180-3p,
hsa-miR-138-5p,
hsa-miR-1258,
hsa-miR-152-3p,
hsa-miR-1264,
hsa-miR-1537-3p,
hsa-miR-1269a,
hsa-miR-154-5p,
hsa-miR-127-5p,
hsa-miR-1-5p,
hsa-miR-181b-5p,
hsa-miR-431-5p,
hsa-miR-1910-5p,
hsa-miR-450a-5p,
hsa-miR-1973,
hsa-miR-4532,
hsa-miR-199b-5p,
hsa-miR-454-3p,
hsa-miR-205-5p,
hsa-miR-4787-3p,
hsa-miR-219a-2-3p,
hsa-miR-497-5p,
hsa-miR-2682-5p,
hsa-miR-520d-3p,
hsa-miR-27a-3p,
hsa-miR-521,
hsa-miR-299-3p,
hsa-miR-522-3p,
hsa-miR-301a-3p,
hsa-miR-548a-5p,
hsa-miR-3127-5p.
hsa-miR-548ad-3p,
hsa-miR-3131,
hsa-miR-548l,
hsa-miR-331-3p,
hsa-miR-553,
hsa-miR-337-5p,
hsa-miR-624-3p,
hsa-miR-34a-5p,
hsa-miR-652-3p,
hsa-miR-3928-3p,
hsa-miR-660-5p,
hsa-miR-424-5p,
hsa-miR-764;
or
(b)
hsa-miR-1258,
hsa-miR-219a-2-3p,
hsa-miR-1264,
hsa-miR-2682-5p,
hsa-miR-1269a,
hsa-miR-27a-3p,
hsa-miR-1302,
hsa-miR-299-3p,
hsa-miR-1306-5p,
hsa-miR-301a-3p,
hsa-miR-138-5p,
hsa-miR-3131,
hsa-miR-152-3p,
hsa-miR-337-5p,
hsa-miR-1537-3p,
hsa-miR-34a-5p,
hsa-miR-154-5p,
hsa-miR-3928-3p,
hsa-miR-1-5p,
hsa-miR-424-5p,
hsa-miR-181b-5p,
hsa-miR-431-5p,
hsa-miR-1910-5p,
hsa-miR-450a-5p,
hsa-miR-1973,
hsa-miR-4532,
hsa-miR-205-5p,
hsa-miR-454-3p,
hsa-miR-4787-3p,
hsa-miR-548ad-3p,
hsa-miR-497-5p,
hsa-miR-548l,
hsa-miR-520d-3p,
hsa-miR-553,
hsa-miR-522-3p,
hsa-miR-624-3p,
hsa-miR-548a-5p,
hsa-miR-764
or
(c)
hsa-miR-1258,
hsa-miR-34a-5p,
hsa-miR-1264,
hsa-miR-424-5p,
hsa-miR-1302,
hsa-miR-431-5p,
hsa-miR-152-3p,
hsa-miR-4532,
hsa-miR-154-5p,
hsa-miR-454-3p,
hsa-miR-181b-5p,
hsa-miR-497-5p,
hsa-miR-1910-5p,
hsa-miR-548a-5p,
hsa-miR-219a-2-3p,
hsa-miR-548ad-3p
hsa-miR-299-3p,
20 . The system according to claim 19 , wherein the one or more algorithms comprises a trained support vector machine (SVM) algorithm trained using samples from the dataset, the SVM is configured to classify the biological sample as belonging to a class corresponding to melanoma if an inner sum of weights and expression of the microRNA is greater than a predetermined threshold.
21 . The system according to claim 19 , wherein the one or more algorithms comprises a nearest-centroid classifier, the nearest-centroid classifier is configured to assign a melanoma class to the biological sample if the centroid of the microRNA of the biological sample is closer to a melanoma centroid of the microRNA instead of a normal centroid of the microRNA.
22 . The system according to claim 19 , wherein the one or more algorithms comprises a compound covariate predictor, the compound covariate predictor is configured to classify the biological sample as belonging to a class corresponding to melanoma if an inner sum of weights and expression of the microRNA is greater than a predetermined threshold. is configured to classify the biological sample as belonging to a class corresponding to melanoma if an inner sum of weights and expression of the microRNA is greater than a predetermined threshold.
23 . A system for determining the disease stage of melanoma, said system comprising:
at least one processor; and at least one storage medium containing program instructions for execution by said processor, said program instructions causing said processor to execute steps comprising: (i) detecting microRNA expression levels in a biological sample, (ii) calculating a staging score (SS) of the biological sample based on a dataset comprising the expression levels of said microRNAs, and (iii) classifying the biological sample as a stage of melanoma based on the value of the staging score wherein the miRNA consist of:
(a)
hsa-let-7e-5p,
hsa-miR-181b-5p,
hsa-miR-105-5p,
hsa-miR-1910-5p,
hsa-miR-1180-3p,
hsa-miR-1973,
hsa-miR-1258,
hsa-miR-199b-5p,
hsa-miR-1264,
hsa-miR-205-5p,
hsa-miR-1269a,
hsa-miR-219a-2-3p,
hsa-miR-127-5p,
hsa-miR-2682-5p,
hsa-miR-1302,
hsa-miR-27a-3p,
hsa-miR-1306-5p,
hsa-miR-299-3p,
hsa-miR-138-5p,
hsa-miR-301a-3p,
hsa-miR-152-3p,
hsa-miR-3127-5p.
hsa-miR-1537-3p,
hsa-miR-3131,
hsa-miR-154-5p,
hsa-miR-331-3p,
hsa-miR-1-5p,
hsa-miR-337-5p,
hsa-miR-34a-5p,
hsa-miR-521,
hsa-miR-3928-3p,
hsa-miR-522-3p,
hsa-miR-424-5p,
hsa-miR-548a-5p,
hsa-miR-431-5p,
hsa-miR-548ad-3p,
hsa-miR-450a-5p,
hsa-miR-548l,
hsa-miR-4532,
hsa-miR-553,
hsa-miR-454-3p,
hsa-miR-624-3p,
hsa-miR-4787-3p,
hsa-miR-652-3p,
hsa-miR-497-5p,
hsa-miR-660-5p,
hsa-miR-520d-3p,
hsa-miR-764
or
(b)
hsa-let-7e-5p,
hsa-miR-299-3p,
hsa-miR-105-5p,
hsa-miR-301a-3p,
hsa-miR-1180-3p,
hsa-miR-3127-5p,
hsa-miR-127-5p,
hsa-miR-331-3p,
hsa-miR-152-3p,
hsa-miR-337-5p,
hsa-miR-1537-3p,
hsa-miR-4787-3p,
hsa-miR-154-5p,
hsa-miR-521,
hsa-miR-199b-5p,
hsa-miR-652-3p,
hsa-miR-27a-3p,
hsa-miR-660-5p
24 . The system according to claim 30 , wherein the staging score is calculated by any algorithm from the group consisting of: logistic regression model, multi-class algorithm comprising four staging classes, nearest centroid classifier, support vector machine and binary decision tree classifier.
25 . The method according to claim 1 wherein the subject is a human.
26 . The method according to claim 1 wherein the biological sample is solid tissue, plasma, blood, skin, exosomes, urine, milk, serum, ascites, cyst fluid, pleural fluid, peritoneal fluid, cerebral spinal fluid, tears, saliva, sputum, hair or combinations thereof.
27 . The method according to claim 4 wherein the subject is a human.
28 . The method according to claim 4 wherein the biological sample is solid tissue, plasma, blood, skin, exosomes, urine, milk, serum, ascites, cyst fluid, pleural fluid, peritoneal fluid, cerebral spinal fluid, tears, saliva, sputum, hair or combinations thereof.
29 . The method according to claim 7 wherein the biological sample is solid tissue, plasma, blood, skin, exosomes, urine, milk, serum, ascites, cyst fluid, pleural fluid, peritoneal fluid, cerebral spinal fluid, tears, saliva, sputum, hair or combinations thereof.
30 . The method according to claim 7 wherein the subject is a human.
31 . The method according to claim 8 wherein said subject is a human.
32 . The method according to claim 10 wherein said agent is selected from one or more of the following:
(i) Immunotherapy, including: Aldesleukin (IL-2), Intron A (Recombinant Interferon Alfa-2b), Ipilimumab, Keytruda (Pembrolizumab), Pembrolizumab, Sylatron (Peginterferon Alfa-2b), Yervoy (Ipilimumab), Zelboraf (Vemurafenib),
(ii) Targeted/small-molecule therapy, including: Cobimetinib, Dabrafenib, Mekinist (Trametinib), Nivolumab (Opdivo), Vemurafenib
(iii) Chemotherapy, including: Dacarbazine
(iv) Viral therapy, including: Imlygic (Talimogene Laherparepvec)
(v) siRNA
(vi) antisense nucleic acids,
(vii) antagonist microRNAs: including, antagomirs,
(viii) enzymatic RNA molecules: including, ribozymes
(ix) miRNA agonist; and/or
(x) anti-miRNA antibodies
33 . The method according to claim 10 wherein said subject is human.Join the waitlist — get patent alerts
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