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Methods and systems for evaluating tumor mutational burden

A mutation load, tumor technology, applied in biochemical equipment and methods, microbial assay/examination, instruments, etc., can solve the problem that whole exome sequencing is not widely available, expensive, time-consuming, etc.

Active Publication Date: 2019-01-11
FOUND MEDICINE INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, translating genomic research into routine clinical practice remains problematic because whole-exome sequencing is not widely available and is expensive, time-consuming, and technically challenging

Method used

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  • Methods and systems for evaluating tumor mutational burden
  • Methods and systems for evaluating tumor mutational burden
  • Methods and systems for evaluating tumor mutational burden

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0639] In embodiments of the methods described herein, a step or parameter in the method is used to modify a downstream step or parameter in the method.

[0640] In one embodiment, the characteristics of the tumor sample are used to modify downstream steps or parameters in one or more or all of: isolation of nucleic acid from said sample; library construction; bait design or selection; hybridization conditions; sequencing; Read mapping; select a mutation calling method; mutation calling; or mutation annotation.

[0641] In one embodiment, the characterization of isolated tumor (or control) nucleic acid is used to modify downstream steps or parameters in one or more or all of: isolation of nucleic acid from said sample; library construction; bait design or selection ; hybridization conditions; sequencing; read mapping; selection of mutation calling methods; mutation calling; or mutation annotation.

[0642] In one embodiment, the characteristics of the library are used to modi...

Embodiment 1

[0801] Example 1: Comparison of Genome-Wide Mutation Burden with Mutation Burden Measured by Targeted Genes

[0802] In this example, it was determined whether TMB measured by comprehensive genome profiling (CGP) testing targeting 315 genes (1.1 Mb of the coding genome) could provide an accurate assessment of exome-wide TMB. Accurate measurements of TMB obtained by a targeted comprehensive genome profiling test are demonstrated.

[0803] method

[0804] Analyzing TCGA data

[0805] TCGA data were obtained from public repositories (Cancer Genome Atlas Research Network et al. Nat Genet 2013;45:1113-20). For this analysis, so-called somatic variants identified by TCGA were used as raw mutation counts. 38Mb was used as an estimate of exome size. For downsampling analyses, using fractions ranging from 0-10 Mb per fraction for the exome at whole exome TMB = 100 mutations / Mb, 20 mutations / Mb, and 10 mutations / Mb A binomial distribution was used to simulate the observed number of...

Embodiment 2

[0813] Example 2: Mutational Burden Landscape by Cancer Type

[0814] In this example, the distribution of TMB across different cohorts of > 100,000 cancer samples is described and the association between somatic alterations and TMB in over 100 tumor types is tested. A subset of patients was found to exhibit high TMB in virtually all cancer disease types, including many rare tumor types. TMB was found to increase significantly with age, showing a 2.4-fold difference between 10 and 90 years. Using a CGP assay targeting the approximately 1.1 Mb coding genome, it was found that there are many disease types in which a significant proportion of patients with high TMB could benefit from immunotherapy.

[0815] This study provides a better understanding of the TMB landscape across human cancers, based on data from comprehensive genomic profiling (CGP) of >100,000 patient tumors of different types. The analysis described in this example expands significantly on existing data quantif...

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Abstract

Methods of evaluating tumor mutational burden in a sample, e.g., a tumor sample or a sample derived from a tumor, from a subject, are disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 301,534, filed February 29, 2016. The content of the aforementioned application is incorporated herein by reference in its entirety. field of invention [0003] The present invention relates to methods of assessing genetic alterations such as tumor mutational burden. Background of the invention [0004] Cancer cells accumulate mutations during cancer development and progression. These mutations can be the result of intrinsic dysfunction of DNA repair, replication or modification or exposure to external mutagens. Certain mutations confer a growth advantage on cancer cells and are positively selected in the microenvironment of the tissue where the cancer arises. Although selection of dominant mutations contributes to tumorigenesis, as the mutations develop, so does the likelihood of the generation of tumor neoantigens and subsequent immune recogn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/50C40B20/04C40B30/00C40B40/06C40B70/00G16B30/10G01N33/574
CPCC40B20/04C40B30/00C40B40/06C40B70/00G16B30/10G01N33/574C12Q1/6806C12Q2600/156C12Q1/6886G16B20/20Y02A90/10C12Q2535/122C12Q2537/165C12Q2565/519C12Q1/6827G16B20/00
Inventor Z·R·查尔默斯C·F·康奈利D·法布里齐奥G·M·弗兰普顿P·赫格德M·科瓦内茨P·J·史蒂芬斯J·X·孙R·耶伦斯基
Owner FOUND MEDICINE INC
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