||5R01CA223978-02 Interpret this number
||Carvajal Carmona, Luis
||University Of California At Davis
||Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer
Gastric cancer (GC) is the third worldwide cause of cancer-related death and a leading cause of cancer related
mortality and morbidity in U.S. Hispanics. Precision GC medicine lags behind most other cancers and there is
an urgent need to further understand its etiology. Addressing existing research gaps will facilitate precision
prevention, treatment, and will improve survival outcomes and disparities. In a recent study, we identified
germline mutations in the homologous recombination (HR) repair genes PALB2, BRCA1 and RAD51C in
multiple GC patients, suggesting that the HR pathway is important in GC risk. Tumors from these patients have
a HR-deficient (HRD) mutational signature, a signature that has been reported in ~7% of sporadic non-
Hispanic white (NHW) tumors. Interestingly, our unpublished data in Hispanics suggest a higher prevalence of
gastric tumors with the HRD phenotype (19%). These recent findings have dual importance in precision GC
medicine as HR gene testing can now be considered in prevention through germline HR gene mutation testing
and patients with HRD tumors may benefit from PARP inhibitors, providing a promising option to the only other
molecularly-guided therapies available for GC treatment. The long-term goal of our program is to generate
knowledge for improving GC outcomes and disparities. The objectives of this application are to identify new
GC genes and to characterize the genomic, clinico-pathological and risk profile of Hispanic gastric tumors and
of gastric HRD tumors in particular. Our hypotheses are that the HR pathway is enriched with GC risk variants
and that Hispanic and HRD GCs have unique genomic profiles. In Aim 1, we will identify germline mutations in
384 familial and early-onset patients of Hispanic origin using targeted sequencing of all HR pathway genes.
Our analyses will focus on identifying the main clinical characteristics of germline HR gene mutation carriers
and on estimating HR gene mutation prevalence and penetrance. In Aim 2, we will conduct exome sequencing
and copy number analyses of paired tumor/normal samples from 300 Hispanic GC patients that were recruited
in a multi-center study in Latin America. The genomic data will be used to identify novel GC drivers that may be
population-specific, to estimate the prevalence of known GC molecular subtypes and driver genes previously
identified in NHWs and to carry out comparisons between molecular phenotypes and the extensive clinical and
risk factor data available in all these samples. In Aim 3, we will compile HRD data from published studies and
from the present study to identify the main clinical, histological and risk factor characteristics of this ?druggable?
tumor type. The proposed study builds on extensive pilot data of newly-discovered HR pathway GC genes. We
will capitalize on our excellent and well-characterized patient resources and samples, which include a high-risk
Hispanic population. This study focuses on a significant cancer disparity and we will generate data essential for
understanding GC genomics and etiology and for the development of molecularly-guided therapies.
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The lancet. Gastroenterology & hepatology, 2018 12; 3(12), p. 874-883.
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