# Large-Scale Genetic Analyses of Human Cancer

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $304,903

## Abstract

PROJECT SUMMARY
 Human cancers are caused by the accumulation of mutations in specific genes. During the previous
funding periods, our group was the first to determine the sequence of protein coding genes in human cancer
and extended this approach to many tumor types. Through this work, we were able to identify candidate genes
which had not been previously linked to tumorigenesis, define the basic genomic and neoantigen landscape
of common human cancers, and point to pathways that underlie the complex genetic alterations in individual
tumor types. More recently, we have identified genomic alterations that are important in the sensitivity and
resistance of common targeted therapies as well as immunotherapy. We have pioneered the development of
non-invasive circulating tumor DNA approaches to detect and monitor tumors, and have shown that these
may be broadly applicable to many cancer patients. These analyses provided new insights into the
mechanisms underlying tumorigenesis and have delineated novel avenues for clinical intervention.
 The recent intersection of cancer genomics with novel immunologic approaches is promising to
revolutionize cancer therapeutics. Immune checkpoint inhibitors have demonstrated notable clinical benefit in
a variety of tumor types and it is thought that these therapies exert their effects in large part through the
immune recognition of mutation associated neoantigens encoded in the genomes of cancer cells.
Unfortunately, despite initial successes, a large fraction of patients do not benefit from these treatments or
develop resistance after an initial response. Our preliminary data suggest that clinical outcome to immune
checkpoint blockade may be determined by the evolving genomic and neoantigen landscape in cancer and
that dynamics of the T cell receptor repertoire may be a useful measure of therapeutic outcome. The purpose
of this competitive renewal application is to extend our large-scale sequencing efforts to focus on
understanding how the evolving genomic and immune landscapes regulate response and resistance to
immune checkpoint blockade. First, we propose genome-wide analyses of tumors to examine cancer genome
changes under the selective pressure of these therapies. We will develop and utilize computational
approaches to predict mutation-associated neoantigens and functionally validate these through novel
approaches in patient-specific T cell cultures. Finally, we will develop non-invasive approaches involving
circulating tumor DNA and the T cell receptor repertoire to dynamically measure response and resistance to
immune checkpoint blockade. The knowledge gained from the studies described in this application will help
to broaden our understanding of the underlying mechanisms of response and resistance to immunotherapy.
We envision that these analyses will be rapidly translated into the clinical setting, providing new approaches
for predicting patient response to current immune-targeted therapies and for develop...

## Key facts

- **NIH application ID:** 10474491
- **Project number:** 5R01CA121113-15
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Valsamo Anagnostou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $304,903
- **Award type:** 5
- **Project period:** 2006-05-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474491

## Citation

> US National Institutes of Health, RePORTER application 10474491, Large-Scale Genetic Analyses of Human Cancer (5R01CA121113-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10474491. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*