Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in the United States,
affecting over a million people annually, and with significant mortality due to metastasis. Despite it prevalence
and high treatment costs, cSCCs are not included in large-scale cancer genomics efforts aimed at
understanding the genetic changes arising in cancer cells, such as The Cancer Genome Atlas (TCGA) project.
Thus, genomic alterations in cSCC have not been comprehensively characterized, and novel, molecularly-
targeted treatments have not been developed. This proposal, modeled after TCGA which is co-led by Dr. Gad
Getz (Co-I of this application), represents the largest effort of its kind to analyze genomic changes that drive
cSCC progression. This critical data is needed to identify targets for novel treatment and prevention strategies
of cSCC. Our team was the first to publish a genome-wide association study that identified ten novel germline
loci associated with increased cSCC risk using the large Genetic Epidemiology Research on Aging (GERA)
cohort. The overall scientific objective of this proposal is to identify and integrate novel tumor
mutational data with previously characterized information on host genetic risk factors and clinical risk
factors to better understand how cancer risk alleles contribute to the development of cSCCs capable of
metastasis. We will analyze 290 cSCCs (145 primary cSCCs that progressed to metastasis and 145 non-
metastatic primary cSCCs) arising in the well-characterized GERA cohort to provide a comprehensive
landscape of genomic alterations in cSCCs. We propose the following specific aims: 1) characterize the
genome and transciptome of 290 cSCCs with existing germline data using a tiered approach including whole-
exome, whole-genome, and RNA sequencing to identify driver mutations, as well as epigenomic changes;; 2)
integrate the somatic mutational analysis with environmental exposure data to understand how environmental
exposures impact cSCCs with distinct somatic mutational profiles;; and 3) develop a clinically meaningful risk
prediction tool for identifying subjects at risk for metastatic cSCCs that combines germline, somatic, and
clinical data. The approach is innovative because it will increase understanding of the joint contribution of the
germline and somatic genomes for cSCC risk and it will create a publicly accessible cSCC genomic data portal
providing a novel resource for the scientific community. The proposed research is significant because it will
integrate germline and somatic genetic data to gain a comprehensive picture of how the genetics of both the
person and the tumor interact to affect cSCC evolution and progression. The comprehensive, integrated
characterization of key genomic changes in one of the most prevalent and costly cancers will support
advances in developing more effective ways to diagnose, treat and prevent cSCCs and potentially squamous
cell carcinoma arising in other organs.
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