Detection of chromosomal abnormalities associated with prognosis of non small cell lung cancer
The methods and compositions described herein address the need for a diagnostic method that can be provided to patients with early stage lung cancer, especially non-small cell lung cancer (NSCLC), to determine whether the patient is at increased risk of poor disease outcome. The methods and compositions thus allow for more informed treatment decisions for the early stage lung cancer patient.
1. A method of predicting disease outcome in a patient being treated for lung cancer, from a biological sample from the patient, the method comprising:
contacting the sample with two or more fluorescent probes, each fluorescent probe targeting a different chromosome subregion, wherein the chromosome subregion is selected from the group consisting of: 1p13.3, 11q13.1, 17q25.1, 2q24.2, 2q33.3, 6p21.2, and 12p13.3;
incubating the two or more fluorescent probes with the sample under conditions in which each fluorescent probe binds selectively with a polynucleotide sequence on its target chromosomal subregion to form a stable hybridization complex;
detecting hybridization of the two or more fluorescent probes, wherein a hybridization pattern showing at least one gain at a chromosomal subregion targeted by the fluorescent probes is indicative of increased risk of poor disease outcome in the patient when compared to a baseline measure of disease outcome in patients having no gain at the two or more chromosomal subregions targeted by the two or more fluorescent probes; and
administering a therapy to the patient that is indicated as having increased risk of poor disease outcome, wherein the patient that is indicated as having increased risk of poor disease outcome is treated post-resection with adjuvant chemotherapy or treated before the resection using neoadjuvant chemotherapy,
wherein the biological sample comprises a tumor sample,
wherein the cancer is stage I-II non-small cell lung cancer (NSCLC), and
wherein the method is carried out by fluorescence in situ hybridization (FISH) with a fluorescent microscope or flow cytometer.
2. The method of claim 1 , wherein a hybridization pattern showing a gain in 1p13.3 and 11q13.1 is indicative of poor disease outcome in the patient.
3. The method of claim 1 , wherein the sample is contacted with a combination of at least three fluorescent probes, each fluorescent probe targeting a different chromosome subregion, wherein a hybridization pattern showing a gain in one or more of the chromosome subregions is indicative of poor disease outcome in the patient.
4. The method of claim 1 , wherein the sample is contacted with a combination of at least four fluorescent probes, each fluorescent probe targeting a different chromosome subregion,
wherein a hybridization pattern showing a gain in one or more of these chromosome subregions is indicative of poor disease outcome in the patient.
5. The method of claim 1 wherein the fluorescent probe combination distinguishes samples comprising stage I-II NSCLC at increased risk of poor disease outcome from samples that do not comprise stage I-II NSCLC at increased risk of poor disease outcome with a sensitivity of at least 93% and a specificity of at least 90%, wherein the sensitivity and specificity is determined using p-values obtained by comparing a decrease in overall survival or in time to recurrence in a patient population with and without the fluorescent probes.
6. The method of claim 5 , wherein the sensitivity is at least 95% and the specificity is at least 90.4%.
7. The method of claim 5 , wherein the sensitivity is at least 96% and the specificity is at least 91%.
8. The method of claim 1 , wherein the probe combination comprises four probes.
9. The method of claim 1 , wherein each fluorescent probe in the fluorescent probe combination is labeled with a different fluorophore.
10. The method of claim 1 , wherein the sample comprises a lung biopsy specimen.
11. The method of claim 1 , wherein each fluorescent probe targets a chromosome subregion selected from the group consisting of Chr 1, 109.5 Mb-111.1 Mb; Chr 11, 64.3 Mb-64.8 Mb; Chr 11, 64.8 Mb-65.7 Mb; Chr 17, 69.2 Mb-71.3 Mb; Chr 2, 159.9 Mb-161.4 Mb; Chr 2, 205.9 Mb-208.1 Mb; Chr 6, 39.1 Mb-39.9 Mb; and Chr 12, 93.7 kb-1.9 Mb.