Sequence variant analysis of cell-free DNA for cancer screening

Abstract

A frequency of somatic mutations in a biological sample (e.g., plasma or serum) of a subject undergoing screening or monitoring for cancer, can be compared with that in the constitutional DNA of the same subject. A parameter can derived from these frequencies and used to determine a classification of a level of cancer. False positives can be filtered out by requiring any variant locus to have at least a specified number of variant sequence reads (tags), thereby providing a more accurate parameter. The relative frequencies for different variant loci can be analyzed to determine a level of heterogeneity of tumors in a patient.

Description

[0001]This application is a continuation of U.S. patent application Ser. No. 15 / 853,288, entitled “SEQUENCE VARIANT ANALYSIS OF CELL-FREE DNA FOR CANCER SCREENING,” filed on Dec. 22, 2017, which is a divisional of U.S. patent application Ser. No. 13 / 801,748, entitled “MUTATIONAL ANALYSIS OF PLASMA DNA FOR CANCER DETECTION,” filed on Mar. 13, 2013, which claims the benefit of U.S. Provisional Patent Application No. 61 / 662,878, entitled “MUTATIONAL ANALYSIS OF PLASMA DNA FOR CANCER DETECTION,” filed on Jun. 21, 2012; U.S. Provisional Patent Application No. 61 / 682,725, entitled “MUTATIONAL ANALYSIS OF PLASMA DNA FOR CANCER DETECTION,” filed on Aug. 13, 2012; U.S. Provisional Patent Application No. 61 / 695,795, entitled “MUTATIONAL ANALYSIS OF PLASMA DNA FOR CANCER DETECTION,” filed on Aug. 31, 2012; and U.S. Provisional Patent Application No. 61 / 711,172, entitled “MUTATIONAL ANALYSIS OF PLASMA DNA FOR CANCER DETECTION,” filed on Oct. 8, 2012, which are herein incorporated by reference i...

AI Technical Summary

Benefits of technology

This patent describes a method to observe mutations in a person's blood to detect cancer. The method uses a technique called random sequencing to measure the frequency of these mutations compared to the person's own DNA. By analyzing these frequencies, the method can categorize the level of cancer and filter out false positive results. The method can also measure the level of heterogeneity in tumors, which is the extent to which multiple mutations occur in a patient's cancer.

Problems solved by technology

When the amount of variations in the bodily fluid exceeds that of the sample with mostly constitutional DNA, there is an increased likelihood that the bodily fluid might contain tumor-derived DNA.

Yet, it is known that sequencing errors can occur and may be misinterpreted as a variation in the constitutional DNA or as mutations derived from tumor DNA.

For example, subjects who are carriers of hepatitis B or C virus have an increased risk of developing hepatocellular carcinoma.

Thus, test subjects who have a similar number or pattern of mutations as a carrier of hepatitis B or C can be considered to have an increased risk of developing hepatocellular carcinoma.

Similarly, subjects who are carriers of human papillomavirus infection have increased risk for cervical cancer, and head and neck cancer.

But, one or more bases of a sequence tag may be in error.

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