Methods for diagnosing a colorectal cancer (CRC) health state or change in CRC health state, or for diagnosing risk of developing CRC or the presence of CRC in a subject
Inventors
Ritchie, Shawn • Goodenowe, Dayan
Assignees
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Publication Number
US-10697969-B2
Publication Date
2020-06-30
Expiration Date
Abstract
The present invention relates to the diagnosis of colorectal and ovarian cancers (CRC and OC, respectively). The present invention describes the relationship between endogenous small molecules and CRC or OC. Specifically, the present invention relates to the diagnosis of CRC and OC through the measurement of vitamin E isoforms and related metabolites. The present invention also relates to diagnostic markers identified in said method. The present invention relates to the underlying case and pre-symptomatic phases of CRC, the diagnosis of various stages and severity of CRC, the early detection of CRC, monitoring and diagnosing the effect of therapy on CRC and OC health states.
Core Innovation
The document describes analytical methods for diagnosing a patient's colorectal cancer (CRC) health state, change in CRC health state, risk of CRC, or presence of CRC in a patient, using blood or serum/plasma measurements of metabolite markers. The approach performs a mass spectrometry assay to obtain a collision induced dissociation (CID) MS/MS fragmentation pattern and quantifying data for one or more metabolite markers, and generates a result that assigns the patient as having or not having CRC, having or not having a change in CRC health state, or having or not having a risk of CRC.
The selected metabolite markers include at least a metabolite having the molecular formula C28H46O4, characterized by a CID MS/MS fragmentation pattern using N2 as collision gas and analyzed under negative ionization comprising daughter ions 445, 383, 427, 401, 223, 205, 177 and 162. The document also describes vitamin E isoform-related endogenous small molecules described as vitamin E-like metabolites, with a semi-saturated chroman ring and a phytyl side chain, and references chromatographic retention times, structural assignments for fragment ions, and chemical structure drawings supporting identification of the marker(s).
The comparative interpretation is that a decrease in the level of the metabolite marker in the patient's blood sample relative to a reference blood sample indicates that the patient has CRC, a change in CRC health state, or is at risk of CRC. The document further describes discovery of differential metabolites by non-targeted FTMS of serum, statistical selection of an optimal biomarker panel, verification by independent LC-MS, and development and validation of a high-throughput targeted MS/MS assay with internal standard normalization and computed patient risk scores.
Claims Coverage
The independent claims cover two CRC analytical methods based on CID MS/MS measurement of blood metabolite markers and comparative interpretation relative to reference data, with the first claim also requiring patient assignment. Across the claims, the main inventive features are the blood assay, the CID MS/MS fragmentation pattern and quantifying data, and the defined C28H46O4 metabolite signature under negative ionization with N2 collision gas.
Comparative crc diagnosis using blood cid ms/ms metabolite markers
Performing a mass spectrometry assay on at least one blood sample using a Fourier transform ion cyclotron resonance, time of flight, magnetic sector, quadrupole or triple quadrupole mass spectrometer to obtain a CID MS/MS fragmentation pattern for one or more metabolite markers and quantifying data; generating a result comprising at least presence or absence of a decrease in the level of the one or more metabolite markers by comparing quantifying data to corresponding data from reference blood samples; and assigning the patient as having or not having CRC, having or not having a change in CRC health state, or having or not having a risk of CRC.
Cid ms/ms fragmentation-defined vitamin e-like metabolite marker signature
Wherein the one or more metabolite marker is at least a metabolite having the molecular formula C28H46O4 and characterized by a CID MS/MS fragmentation pattern using N2 as collision gas and analyzed under negative ionization comprising daughter ions 445, 383, 427, 401, 223, 205, 177 and 162, and wherein a decrease in the level of the one or more metabolite marker relative to a reference blood sample indicates CRC, a change in CRC health state, or risk of CRC.
Crc disease marker detection using cid ms/ms blood metabolite marker quantification
Providing at least one blood sample from a patient and performing a mass spectrometry assay on the at least one blood sample using a Fourier transform ion cyclotron resonance, time of flight, magnetic sector, quadrupole or triple quadrupole mass spectrometer to obtain a CID MS/MS fragmentation pattern for one or more metabolite markers and quantifying data for the one or more metabolite markers, wherein the one or more metabolite marker is at least C28H46O4 characterized by a CID MS/MS fragmentation pattern using N2 as collision gas and analyzed under negative ionization comprising the daughter ions 445, 383, 427, 401, 223, 205, 177 and 162.
The independent claims cover CRC analytical methods based on targeted CID MS/MS measurement of blood metabolite markers characterized by the molecular formula C28H46O4 and a specific set of daughter ions under negative ionization using N2 collision gas. The first independent claim further requires comparing quantified data to reference blood samples to determine presence or absence of decreased marker level and assigning CRC presence, CRC health-state change, or CRC risk; the second independent claim covers detection of a CRC disease marker using the same CID MS/MS metabolite-marker signature and quantifying data from blood.
Stated Advantages
Enables diagnosing a patient's colorectal cancer (CRC) health state, or change in CRC health state.
Enables diagnosing risk of CRC or the presence of CRC in a patient.
Enables detecting a colorectal cancer (CRC) disease marker.
Documented Applications
Diagnosing a patient's colorectal cancer (CRC) health state, or change in CRC health state.
Diagnosing risk of CRC or presence of CRC in a patient.
Detecting a colorectal cancer (CRC) disease marker.
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