To prevent cancer, USC researchers look beyond traditional risk factors

To prevent cancer, USC researchers look beyond traditional risk factors

September 15, 2020


By Sarah Nightingale

Researchers at USC Norris Comprehensive Cancer Center are integrating “big data” related to multiple cancer risk factors to predict cancer occurrence and to help reduce risk in susceptible populations. 

Why me? It’s a question doctors hear all the time when they diagnose people with cancer. If only the answer were simple.

“Cancer — which is the uncontrolled growth of abnormal cells in the body — is a set of different diseases that arise from a complex interplay among environmental, genomic, lifestyle and sociodemographic factors,” said Caryn Lerman, the H. Leslie and Elaine S. Hoffman Cancer Research Chair and associate dean for cancer programs at the Keck School of Medicine of USC. Lerman joined USC in March 2019 as the director of the USC Norris Comprehensive Cancer Center.

“While medical research has considerably advanced our understanding of cancer etiology, there is now a tremendous opportunity to translate this knowledge into precision cancer prevention in different ethnic and racial populations,” she added.

Among the first eight cancer centers to be designated by the National Cancer Institute in 1973, the nationally recognized USC Norris cancer center has been a leader in advancing what we know about cancer — a diagnosis received by 1.7 million Americans each year. USC Norris cancer center researchers have led and contributed to studies demonstrating the role of tobacco, physical activity and diet and obesity, among many other cancer risk factors. USC Norris investigators have also advanced our understanding of the genomic factors contributing to cancer risk.

To read full article on USC News, click HERE. 

New DNA Sequencing technique may help unravel genetic diversity of cancer tumors

New DNA sequencing technique may help unravel genetic diversity of cancer tumors

June 25, 2020

By Laura LeBlanc

The ability to sequence the genome of a tumor has revolutionized cancer treatment over the last 15 years by identifying drivers of cancer at the molecular level. But understanding the genetic diversity of individual cells within a tumor and how that might impact the disease progression has remained a challenge, due to the current limitations of genomic sequencing. Using a microfluidic-droplet-based single cell sequencing method, USC researchers have simultaneously sequenced the genomes of close to 1,500 single cells, revealing genetic diversity previously hidden in a well-studied melanoma cell line.

The study, just published in Nature Communications Biology, demonstrates the ability of single-cell sequencing to reveal possible evolutionary trajectories of cancer cells.  

“We used this approach to examine a standard cancer cell-line, examined thousands of times by many different labs,” said David Craig, PhD, co-director of the Institute of Translational Genomics at Keck School of Medicine of USC and study author. “What was really surprising here was with this technology we uncovered complexity we did not expect. This line actually consistently became a mixture of different types of cells. Re-examining decades of prior work on this line — now with this new information — we have new insights into tumor evolution.”

Getting a high-resolution view of cancer’s complexity

Currently, the genetic information of a tumor is typically obtained by sequencing millions of tumor cells together, rather than individually. While this method offers a broad view of the genetic makeup of the tissue, it can miss small populations of cancer cells within a tumor that are different from the majority of cells.

With other approaches that analyze the DNA of individual cells, the process is laborious, taking weeks to process just a few cells and requiring resources that most laboratories do not have.

For this study, researchers used an emerging technique called “single-cell copy number profiling.” developed by 10X Genomics with novel analysis methods that integrated these results with those of historical methods.

“Instead of analyzing tissue DNA that is the average of thousands of cells, we analyzed the individual DNA of close to 1,500 cells within a single experiment,” said Dr. Enrique Velazquez-Villarreal, lead author and assistant professor of translational genomics at the Keck School. “Studying cancer at this higher resolution, we can discover information that lower-resolution bulk sequencing misses.”

Their analysis revealed at least four major sub-populations of cells, also known as clones, that are expected to have, at some point during the cancer cell line’s evolution, mutated from the original cancer cell.  

The ability to identify sub-clones in cancer tissue could provide important biological insights into how cancer progresses, how it spreads and why it can become resistant to treatment.

“What if there’s a small population of cells in a tumor that has acquired a change that makes them resistant to therapy? If you were to take that tumor and just grind it up and sequence it, you may not see that change,” said John Carpten, PhD, study author and  Co-Leader of the Translational and Clinical Sciences Program at the USC Norris Comprehensive Cancer Center, Chair of the Department of Translational Genomics, Keck School of Medicine, and Co-Director of the USC Institute for Translational Genomics. “If you go to the single cell level, you not only see it, but you can see the specific population of cells that has actually acquired that change. That could provide earlier access to the molecular information that could help define treatment approaches.”

The researchers plan to share their data in the hope that more cancer researchers will focus on single-cell sequencing. They are also using their technique to study genetic diversity in clinical cancer specimens as a way to better understand the early molecular changes that lead to aggressive and tough-to-treat advanced cancers.

About this study

In addition to Craig, Velazquez-Villarreal and Carpten, the study‘s other authors include Shamoni Maheshwari, Jon Sorenson, Ian T. Fiddes, Vijay Kumar, Yifeng Yin, and Claudia Catalanotti of 10x Genomics; and Mira Grigorova of Hutchison-MRC Research Centre, University of Cambridge; and Paul A. Edwards  of Hutchison-MRC Research Centre, University of Cambridge and Cancer Research UK Cambridge Institute.

This study was supported by 10x Genomics, the Norris Comprehensive Cancer Center, and the Department of Translational Genomics at Keck School of Medicine of University of Southern California.

Inherited mutation associated with higher prostate cancer risk in African American families

Inherited mutation associated with higher prostate cancer risk in African American families

June 8, 2020

By Laura LeBlanc

For years, researchers have known that men of African ancestry are at greater risk of developing prostate cancer with research suggesting that inherited factors may contribute to their greater risk. 

Now, a new USC study published in European Urology is the first to identify an inherited genetic variant associated with higher risk of prostate cancer in men of African descent that contributes to the clustering of prostate cancer cases within families.

“About 12% of men of African ancestry carry this particular variant in the genome, which increases their risk two-fold. The variant is not found in other populations,” said Christopher Haiman, ScD, co-leader of the Cancer Epidemiology Program at the USC Norris Comprehensive Cancer Center, study author and Professor of Preventive Medicine at the Keck School of Medicine of USC. “But it’s even more common in families with a history of prostate cancer.”

African American men at higher risk

One in six African American men develops prostate cancer in his lifetime. African American men are 1.8 times more likely to be diagnosed with—and 2.2 times more likely to die from—prostate cancer than white men. If a black man’s brother or father had prostate cancer, his risk will be even higher. But until now, there has been no genetic mutation or biomarker doctors could look for to determine if a particular African American man was more likely to get the disease.

While a prostate specific-antigen (PSA) blood test can detect prostate cancer, many of the cancers it detects may not cause harm, while treatment can cause life-altering side effects.

In the study, which is part of the RESPOND African American prostate cancer initiative, researchers looked at 9,052 prostate cancer cases among men of African ancestry. More than 23 percent had this specific genetic variant. The variant was strongly associated with a prostate cancer diagnosis at an earlier age, more aggressive disease, and men with a family history of prostate cancer. In fact 32 percent of the men with prostate cancer who had a family history of the disease carried the variant.

Variant could aid in screening and treatment decisions

This new information may eventually help clinicians identify men who could benefit from early prostate cancer screening and treatment.

“A man of African ancestry comes in and says, ‘Well, I have prostate cancer and I have a family history of the disease. Why?’ Well, now there’s a variant you can test to see if they and their family members carry it,” said Haiman. “This is a marker that down the road may be used to identify African-Americans and their family members who are at high risk and would benefit from more precise, targeted, and earlier PSA screening.”

Researchers believe this variant is one of the reasons why African American men are more likely to get prostate cancer and hope to find out more about the role genetic mutations play in their overall risk.

About this study

In addition to Haiman, the study’s other authors include Burcu F. Darst, Peggy Wan, Xin Sheng, Sue A. Ingles, John Carpten, Mariana C. Stern, David V. Conti, Susan M. Gundell, Loreall Pooler and Lucy Xia of the Keck School of Medicine of USC; Jeannette T. Bensen and James L. Mohler of University of North Carolina at Chapel Hill; Benjamin A. Rybicki and Christine Neslund-Dudas of Henry Ford Hospital; Barbara Nemesure and Anselm J.M. Hennis of Stony Brook University; Esther M. John of Stanford University School of Medicine; Jay H. Fowke of The University of Tennessee Health Science Center; Victoria L. Stevens and Susan M. Gapstur  of the American Cancer Society; Sonja I. Berndt, Meredith Yeager and Stephen J. Chanock of the National Cancer Institute, National Institute of Health; Chad D. Huff and Sara S. Strom, of the University of Texas MD Anderson Cancer Center; Jong Y. Park, Thomas A. Sellers and Kosj Yamoah of the Moffitt Cancer Center and Research Institute; Wei Zheng, Melinda C. Aldrich, Peter E. Clark and William J. Blot of the Vanderbilt University School of Medicine; Elaine A. Ostrander of the National Human Genome Research Institute, National Institutes of Health; Patrick C. Walsh and William B. Isaacs of the Johns Hopkins Hospital and Medical Institutions; Shiv Srivastava, Gyorgy Petrovics and Jennifer Cullen of the Uniformed Services University of the Health Sciences; Adam B. Murphy of Northwestern University; Maureen Sanderson of Meharry Medical College; Dana C. Crawford and William S. Bush of Case Western Reserve University; Olivier Cussenot and Geraldine Cancel-Tassin of CeRePP; Rick A. Kittles of the City of Hope Comprehensive Cancer Center; Jianfeng Xu of the NorthShore University HealthSystem; Zsofia Kote-Jarai, Koveela Govindasami and Rosalind A. Eeles of the Institute of Cancer Research; Anand P. Chokkalingam of the University of California, Berkeley; Luc Multigner, Florence Menegaux, Pascal Blanchet and Laurent Brureau of Inserm; Marie-Elise Parent of INRS-Institut Armand-Frappier; Adam S. Kibel of the Dana-Farber Cancer Institute; Eric A. Klein of the Cleveland Clinic; Phyllis J. Goodman and Janet L. Stanford of the Fred Hutchinson Cancer Research Center; Bettina F. Drake of the Washington University School of Medicine; Jennifer J. Hu of the University of Miami Miller School of Medicine; Graham Casey of the University of Virginia; Alexander Lubwama and Stephen Watya of the Makerere University College of Health Sciences; Ian M. Thompson Jr and Robin Leach of the University of Texas Health Science Center; Elizabeth T.H. Fontham and Diptasri Mandal of Louisiana State University Health Sciences Center; Gary J. Smith of the Roswell Park Cancer Institute; Jack A. Taylor of the National Institute of Environmental Health Services; Kathleen Cooney of Duke University of Medicine.

This study was supported the National Cancer Institute at the National Institutes of Health (grants U19 CA148537, U19 CA214253, R01 CA165862, and K99 CA246063). Dr. Burcu F. Darst was supported in part by an award from the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter.