Genetic Analysis of Remote Population May Advance Breast Cancer Prevention and Treatment

Luis Carvajal-Carmona, PhD

Assistant Professor

Department of Biochemistry and Molecular Medicine

There are people living in remote regions of the Andes who have been relatively isolated for more than 500 years. Their homogeneity and long lines of ancestors make these populations excellent subjects for genetics research. The region already is the center of important research, including the world’s largest chemoprevention trial for Alzheimer’s disease. Over the past 5 years, I have studied these remote populations, looking for genetic mutations that may signal a higher risk for cancer—information that also can be used to develop genetic screening tests for cancer risk and to explore new avenues for development of targeted therapies.

Using blood samples collected from the Andean villagers, my laboratory at the UC Davis Genome Center uses a variety of high-throughput genetic analysis techniques to screen for genetic differences.

With support from UC Davis, GSK Oncology, and V Foundation grants, we are working to identify new genes associated with breast cancer. Plans are in place to validate relevancy of the discoveries through partnerships with other investigators at UC Davis, Stanford, UCSF, University of Southern California, and the Cancer Prevention Institute of California. Our work has already revealed interesting background on the history and ancestry of these villagers.

Studies of maternal lines through mitochondrial DNA as it is passed from mothers to children have shown that ancestral mothers were primarily Native American. More surprising is the paternal lineage. Our testing in men found that almost all the genetic makeup of the Y chromosome DNA is European in origin.

It is likely that male Spanish conquistadors settled in the area, taking Native American women as wives. The male Native American population was presumably decimated from disease and conflict. Few European women came to the area, so the European men married the remaining Native American women, each passing on their genetic lines. These findings are among the most striking examples of male-driven directional mating in humans and have been subsequently replicated by many researchers in other Hispanic populations.

The homogeneity of these Andean villagers means there are large families with the same cancers caused by very few mutations passed down by village ancestors. We have screened 191 women with breast cancer in Colombia and identified 25 patients and families with the same genetic mutation in the BRCA1 gene. Genealogical studies indicate the mutation was likely introduced by a Spanish ancestor who settled in the Huila Province and whose descendants still live in the region. We are now using modern genome sequencing methods to identify mutations in new genes as we expect that many more “founder mutations” are still undiscovered and will give us clues about genetic susceptibility to cancer and its biology.

At UC Davis, we are working with oncologist Helen Chew, MD, leader of the Clinical Breast Cancer Program, to identify genes associated with cancer treatment-related toxicity through analysis of the genomes of an estimated 400 breast cancer patients being treated with aromatase inhibitors, which can cause serious joint and muscle aches. We hope to identify genes that will enable physicians to predict which patients are at higher risk of developing these side effects, which can hamper treatment compliance and effectiveness.

We also plan to conduct pharmacogenetic studies for breast cancer and the role of DNA repair variation on patterns of cancer susceptibility. The latter study will involve collaborations with Wolf-Dietrich Heyer, PhD, associate director for Basic Research at UC Davis Cancer Center and chair of the Department of Microbiology and Molecular Genetics, and with colleagues at Kaiser Permanente.

We also hope that our quest for cancer-causing genetic mutations will help reduce cancer health disparities worldwide and fill a research void. Cancer is becoming a looming health crisis in Latin America and many other developing countries, where rates are rising as life expectancy increases. At the same time, few resources have been devoted to cancer screening, prevention, and treatment, making death rates from the disease much higher than in Europe and the United States. Our colon and breast cancer research already has helped affected family members understand the need for regular screening.

In addition, we expect this work will benefit the US Hispanic population, given their shared ancestry with Latin Americans. Identification of cancer mutations common in Latin America, for instance, could help in developing rapid screening methods or more personalized treatments in US Hispanics. Now is the most exciting time to conduct cancer research. We hope that our studies benefit the people from these remote regions and contribute to improving cancer prevention and treatment worldwide, as novel cancer gene discoveries will open new avenues for research and the development of better therapies and treatments.