Compositions, methods and kits for diagnosis of lung cancer
Methods are provided for identifying biomarker proteins that exhibit differential expression in subjects with a first lung condition versus healthy subjects or subjects with a second lung condition. Also provided are compositions comprising these biomarker proteins and methods of using these biomarker proteins or panels thereof to diagnose, classify, and monitor various lung conditions. The methods and compositions provided herein may be used to diagnose or classify a subject as having lung cancer or a non-cancerous condition, and to distinguish between different types of cancer (e.g., malignant versus benign, SCLC versus NSCLC).
1. A method of determining the likelihood that a pulmonary nodule in a subject is not lung cancer, comprising:
(a) contacting a blood sample obtained from the subject with a proteolytic enzyme to produce peptide fragments from a panel of proteins present in the blood sample, wherein the panel comprises C163A and LG3BP;
(b) combining the produced peptide fragments from the panel from step (a) with labeled, synthetic peptide fragments which correspond to the produced peptide fragments from the panel;
(c) performing selected reaction monitoring mass spectrometry to measure the abundance of the peptide fragments from step (b);
(d) calculating a probability of lung cancer score based on the peptide fragment measurements of step (c) and clinical risk factors comprising age, smoking status, nodule diameter, nodule spiculation status and nodule location; and
(e) ruling out lung cancer for the subject if the score in step (d) is lower than a pre-determined score; wherein the said score is determined as XL 2(k), for a subject k, wherein
XL_
2
(
k
)
=
{
max
(
0
,
p
(
k
)
-
0
.
5
)
,
log
2
(
LG
3
BP
C
163
A
)
≤
.38
p
(
k
)
,
log
2
(
LG
3
BP
C
163
A
)
>
.38
p
(
k
)
=
e
X
1
+
e
X
X=6.8272+0.0391* Age+0.7917* Smoker+0.1274* Diameter+1.0407* Spiculation+0.7838* Location
wherein Age is the age of the subject in years, Smoker is 1 if the subject is a former or current smoker otherwise 0, Diameter is the size of the lung nodule in mm, Spiculation is 1 if the lung nodule is spiculated otherwise 0 and Location is 1 if the lung nodule is located in an upper lung lobe otherwise 0.
2. The method of claim 1 , wherein when lung cancer is ruled out, the subject is monitored periodically.
3. The method of claim 1 , wherein the subject has low to moderate cancer risk.
4. The method of claim 1 , further comprising a physician's assessment of cancer risk.
5. The method of claim 4 , wherein the subject is assigned a physician's assessment of cancer risk from between 0 to 1.
6. The method of claim 2 , wherein the periodic monitoring is a pulmonary function test (PFT), pulmonary imaging, a biopsy or any combination thereof.
7. The method of claim 6 , wherein said pulmonary imaging is an x-ray, a chest computed tomography (CT) scan, or a positron emission tomography (PET) scan.
8. The method of claim 1 , wherein said pulmonary nodule has a diameter of less than or equal to 3 cm.
9. The method of claim 1 , wherein said pulmonary nodule has a diameter of about 0.8 cm up to 3.0 cm.
10. The method of claim 1 , wherein the selected reaction monitoring mass spectrometry is performed using an antibody that specifically binds the peptide fragments being detected.
11. A method of determining the likelihood that a pulmonary nodule in a subject is lung cancer, comprising:
(a) contacting a blood sample obtained from the subject with a proteolytic enzyme to produce peptide fragments from a panel of proteins present in the blood sample, wherein the panel comprises C163A and LG3BP;
(b) combining the produced peptide fragments from the panel from step (a) with labeled, synthetic peptide fragments which correspond to the produced peptide fragments from the panel;
(c) performing selected reaction monitoring mass spectrometry to measure the abundance of the peptide fragments from step (b);
(d) calculating a probability of lung cancer score based on the peptide fragment measurements of step (c) and clinical risk factors comprising age, smoking status, nodule diameter, nodule spiculation status and nodule location; and
(e) ruling in lung cancer for the subject if the score in step (d) is equal to or higher than a pre-determined score;
wherein the said score is determined as XL 2(k), for a subject k, wherein
XL_
2
(
k
)
=
{
max
(
0
,
p
(
k
)
-
0
.
5
)
,
log
2
(
LG
3
BP
C
163
A
)
≤
.38
p
(
k
)
,
log
2
(
LG
3
BP
C
163
A
)
>
.38
p
(
k
)
=
e
X
1
+
e
X
X=6.8272+0.0391* Age+0.7917* Smoker+0.1274* Diameter+1.0407* Spiculation+0.7838* Location
wherein Age is the age of the subject in years, Smoker is 1 if the subject is a former or current smoker otherwise 0, Diameter is the size of the lung nodule in mm, Spiculation is 1 if the lung nodule is spiculated otherwise 0 and Location is 1 if the lung nodule is located in an upper lung lobe otherwise 0.
12. The method of claim 11 , wherein when lung cancer is ruled in, the subject is monitored periodically.
13. The method of claim 11 , wherein the subject has low to moderate cancer risk.
14. The method of claim 11 , further comprising a physician's assessment of cancer risk.
15. The method of claim 14 , wherein the subject is assigned a physician's assessment of cancer risk from between 0 to 1.