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Identification and use of circulating nucleic acid tumor markers

Pending Publication Date: 2022-06-23
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0037]Identifying the plurality of genomic regions may comprise for each genomic region in the plurality of genomic regions, ranking th

Problems solved by technology

While sensitive, such methods require optimization of molecular assays for each patient, limiting their widespread clinical application.
While powerful, these approaches are limited by the number of mutations that can be interrogated (Rachlin et al.
The methods are limited to monitoring somatic chromosomal rearrangements, however, and must be personalized for each patient, thus limiting their applicability and increasing their cost.
While this technique provides high sensitivity and specificity, this method is for single mutations and thus any given assay can only be applied to a subset of patients and/or requires patient-specifi

Method used

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  • Identification and use of circulating nucleic acid tumor markers
  • Identification and use of circulating nucleic acid tumor markers
  • Identification and use of circulating nucleic acid tumor markers

Examples

Experimental program
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Effect test

Example

Example 1

An Ultrasensitive Method for Quantitating Circulating Tumor DNA with Broad Patient Coverage

[0781]Circulating tumor DNA (ctDNA) represents a promising biomarker for noninvasive detection of disease burden and monitoring of recurrence. However, existing ctDNA detection methods are limited by sensitivity, a focus on small numbers of mutations, and / or the need for patient-specific optimization. To address these shortcomings, CAncer Personalized Profiling by Deep Sequencing (CAPP-Seq) was developed, an economical and highly sensitive method for quantifying ctDNA in plasma in nearly every patient. We implemented CAPP-Seq for non-small cell lung cancer (NSCLC) with a design that identified mutations in >95% of tumors, simultaneously detecting point mutations, insertions / deletions, copy number variants, and rearrangements. When tumor mutation profiles were known, we detected ctDNA in 100% of pre-treatment plasma samples from stages II-IV NSCLC and 50% of samples from stage I NSCLC,...

Example

Example 2

Designing a Personalized Selector Set

[0879]In certain circumstances, monitoring tumor burden in a patient known to have cancer is likely to be impractical using an ‘off-the-shelf’ strategy applying knowledge from a cohort of patients with the same tumor type, to selectively capture genomic regions that are recurrently mutated in that tumor type using CAPP-Seq. These situations include, but are not limited to, cases where (1) the tumor is of an unknown primary histology (e.g., CUP); (2) the histology is known, but is too rare to have a sufficient number of patients with that tumor type previously profiled to define the average patient's tumor somatic genetic landscape (e.g., soft tissue sarcoma subtyped); (3) the histology is known but the average / median number of recurrent somatic lesions in that tumor type are too low to achieve desired sensitivity levels (e.g., pediatric tumors, etc.); or (4) the histology is known and the average / median number of recurrent somatic lesion...

Example

Example 3

Use of a Selector Set to Diagnose a Cancer

[0881]A plasma sample is obtained from a female subject with an abnormal lump in her breast. Cell-free DNA (cfDNA) is extracted from the plasma sample. An end repair reaction is performed on the cfDNA by mixing the components in a sterile microfuge tube (or other suitable sterile container) as follows:

ComponentVolume (μL)cfDNA1-75Phosphorylation Reaction Buffer (10X)10T4 DNA polymerase5T4 Polynucleotide kinase5dNTPs4DNA Polymerase I, Large (Klenow)1Sterile H2O-bring total volume up to 100 μL

[0882]The end repair reaction mixture is incubated in a thermal cycler for 30 minutes at 20° C.

[0883]Clean-up of the end repaired cfDNA is performed by adding 160 μL (1.6×) of resuspended AMPure XP beads to the end repair reaction mixture. The AMPure beads are mixed into the solution on a vortex mixer or by pipetting up and down (e.g., 10 times or more). The reaction is incubated for 5 minutes at room temperature. The reaction is placed on a magn...

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Abstract

Methods for creating a selector of mutated genomic regions and for using the selector set to analyze genetic alterations in a cell-free nucleic acid sample are provided. The methods can be used to measure tumor-derived nucleic acids in a blood sample from a subject and thus to monitor the progression of disease in the subject. The methods can also be used for cancer screening, cancer diagnosis, cancer prognosis, and cancer therapy designation.

Description

STATEMENT OF GOVERNMENTAL SUPPORT[0001]This invention was made with Government support under contract W81XWH-12-1-0285 awarded by the Department of Defense. The Government has certain rights in the invention.BACKGROUND OF THE INVENTION[0002]Tumors continually shed DNA into the circulation, where it is readily accessible (Stroun et al. (1987) Eur J Cancer Clin Oncol 23:707-712). Analysis of such cancer-derived cell-free DNA (cfDNA) has the potential to revolutionize detection and monitoring of cancer. Noninvasive access to malignant DNA is particularly attractive for solid tumors, which cannot be repeatedly sampled without invasive procedures. In non-small cell lung cancer (NSCLC), PCR-based assays have been used previously to detect recurrent point mutations in genes such as KRAS or EGFR in plasma DNA (Taniguchi et al. (2011) Clin. Cancer Res. 17:7808-7815; Gautschi et al. (2007) Cancer Lett. 254:265-273; Kuang et al. (2009) Clin. Cancer Res. 15:2630-2636; Rosell et al. (2009) N. En...

Claims

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Application Information

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IPC IPC(8): C12Q1/6886G16B30/00C12Q1/6806C12Q1/6855C12Q1/6827G16B30/10
CPCC12Q1/6886G16B30/00C12Q1/6806C12Q2600/156C12Q1/6827G16B30/10C12Q1/6855C12Q2525/179C12Q2525/191C12Q2535/122C12Q2537/159C12Q2537/165C12Q2563/131C12Q2563/179
Inventor DIEHN, MAXIMILIANALIZADEH, ARASH ASHNEWMAN, AARON M.BRATMAN, SCOTT V.
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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