The Carvajal-Carmona laboratory works on the genetics of human diseases using several approaches including linkage analysis, candidate gene and genome-wide association studies, admixture mapping, germline and tumor sequencing and a number of "omics" technologies. Our research studies are highly collaborative and draw expertise from several fields including genetics, statistics, epidemiology, bioinformatics and genomics. We collaborate with several groups in Europe, Asia and the Americas. We are also establishing several local collaborations at UC Davis Comprehensive Cancer Center and the School of Biological Sciences.

The main focus of our studies has been human cancer. We have shown, in the past, the existence of several risk alleles that increase the probability of cancer using genome-wide linkage and association studies using SNP- array based designs. At UC Davis, we are continuing with these gene-hunting efforts and are primarily using approaches based on next-generation sequencing, given the excellent facilities in our Genome Center. Below, there is a brief description of our main ongoing projects, most of which are in the need of enthusiastic graduate students and postdocs (We are hiring!).

Colorectal Cancer

At our lab, we are currently working on building onto the largest resource used to study the genetics of colorectal cancer in the Hispanic population. Colorectal cancer is an important cause of mortality and morbidity in the country. The risk of colorectal cancer is partially mediated by a genetic predisposition. It is hoped that once most of the colorectal cancer genes are identified, such information can be used to improve prevention and treatment. We have working at the forefront of colorectal cancer genetics and have been involved in the discovery of nearly all SNPs that increase the risk of this malignancy in the Caucasian population. At UC Davis, we are continuing with our gene identification efforts, using samples from our studies in Latin America. Specifically, we are sequencing whole exomes from early-onset cases from Hispanic isolates and from multi-case families that do not have mutations in any of the known colorectal cancer genes. We also have an active participation in the CHIBCHA study, the largest admixture mapping study that is being carried out in the Hispanic population. In addition to gene identification efforts, we also have plans to investigate the function of CRC alleles using expression quantitative mapping studies and other "omics" approaches.

Breast Cancer

Breast cancer is the most common malignancy in women and about a third of the risk is accounted by genetic variation, most of which is still unknown. We are currently using genetics to identify novel causes of breast cancer, investigate pharmacogenetic responses and address health disparities among various populations. Interestingly, the risk of disease, as well as the way in which cancer presents, varies between populations. For example, women from Hispanic populations from the USA and Latin America tend to present with cancer at much earlier ages, suggesting the existence of genetic elements that are involved in disease predisposition. Furthermore, breast cancers in Hispanics are diagnosed at later stages, when compared to other ethnic groups, and generally have worse prognoses. Interestingly, previous studies have shown that the risk of breast cancer in Hispanics is associated with a higher European ancestry. Our group is currently engaged in similar studies in the Colombian population and is aiming to identify breast cancer genes using admixture mapping. At UC Davis, we are also currently planning to use next generation sequencing to identify new breast cancer genes in this population using exome sequencing. We also have planned studies on pharmacogenetics of aromatase inhibitors (In collaboration with Dr. Helen Chew at the UC Davis Comprehensive Cancer Center) and on functional genomics and epidemiology of variation in the DNA double-strand break repair pathway.

Thyroid Cancer

Thyroid cancer, an epidemic and highly genetic malignancy, accounts for ~2% of all diagnosed cancers in the USA, is the most common endocrine malignancy in the country, and its incidence is increasing at a very fast rate (4.5% per year). Thyroid cancer is three times more common in women. In American women; thyroid cancer is the 6th most commonly diagnosed malignancy (~50K new cases/year) and the 4th most prevalent cancer. About half a million Americans have or have had thyroid cancer and therefore, this cancer is becoming an important public health issue in the USA. Among common malignancies, thyroid cancer has the strongest familial risk and thus is highly amenable for gene mapping studies. The identification of thyroid cancer genes will be crucial to establish personalized medical programs and to discover pathways that can be targeted for therapeutic development. One of the long-term aims of our research group will be to work in this unique and promising cancer genetics research niche. We are currently planning to carry out the following studies on this condition: i) Identification of susceptibility variants in thyroid stem cell genes using targeted sequencing; ii) Investigation of associations between genetic ancestry and cancer risk in Hispanics using a panel of ancestry informative markers and; iii) Identification of new high and moderate penetrance loci using exome sequencing in familial cases.

Gastric Cancer

Gastric cancer is the second most common cause of cancer death worldwide. The incidence of gastric cancer varies across populations, with the highest incidence reported in Asia, Latin America and in some European countries such as Portugal. Our group currently has two main projects on gastric cancer genetics, focused on identifying new familial forms of gastric cancer and sequencing tumors in Hispanic populations. One of them is being carried out in collaboration with Dr. Manuel Teixeira in the Portuguese Institute of Oncology, and involves exome sequencing of index cases from 16 Portuguese families who do not have CDH1 mutation (the only known gastric cancer gene) but that appear to be segregating a monogenic form of the disease. The second project is in collaboration with colleagues in Colombia and has initially a dual purpose: i) to investigate associations between ancestry and cancer risk in Hispanics using ancestry informative markers and; ii) to understand the patterns of somatic mutations in Hispanic gastric tumors using exome sequencing. The No Stomach for Cancer foundation awarded a $50,000 grant to Dr. Carvajal-Carmona for a study titled 'Gastric cancer gene identification through haplotype analysis and sequencing'. Gastric cancer is the fourth leading cause of cancer related deaths and approximately ~10% of cases show familial clustering. So far, mutations in gene CDH1 are the only known cause of familial gastric cancer (Hereditary Diffuse Gastric Cancer or HDGC), that explain only 25% of familial cases. Through this study we aim to identify missing heritability in CDH1 negative familial gastric cancer cases by performing exome sequencing and identity-by-descent analysis on cases recruited from population isolates in Portugal and Spain.

Single Cell Sequencing

Cancer is a heterogeneous disease consisting of subclonal populations at the genetic level that possess a selective growth advantage over normal tissue. Furthermore, these subclones have differential responses to therapeutic interventions, particularly molecularly targeted approaches to treatment. Traditional cancer genomics techniques obtain sequence data at a single time point from bulk tumor tissue. This method provides a snapshot of somatic mutational profiles at the population level, but is limited in its sensitivity to detect rare and potentially important subclones by sample quality, sequencing depth, and subclonal population frequency. However, recent technological advances in the field of single cell genomics now allow for the interrogation of genetic aberrations at a single cell resolution in a high throughput fashion, providing the technical means to fully map the clonal architecture of solid tumors. Furthermore, the lack of temporal resolution makes the identification of mutations that provide a selective growth advantage more challenging, hindering the search for driver mutations. Serial sampling of single cells from a tumor over time and after therapeutic bottlenecks has the potential to provide important insights into the molecular processes underlying cancer development as well as resistance to therapy. To this end, we perform exome sequencing of single tumor cells isolated from patient derived xenograft (PDX) models to evaluate tumor heterogeneity before and after therapy. The high genetic diversity may explain why this heterogeneous tumors can be so difficult to treat as each tumor can be composed of many individual subclones that can become dominant under selective pressures, such as cytotoxic therapy, resulting in relapse.