Investigators at Weill Cornell Medicine have identified significant differences in the molecular characteristics of tumors from younger and older patients with cancer across several cancer types. Their research, published by Shah et al in Cell Reports, suggests that cancer treatment could potentially be tailored by age. The study also identified preexisting drugs that could target mutations predominantly found in younger patients with cancer.
“Our study is the first to investigate distinct age-related differences in tumor characteristics across a broad range of cancers,” said senior author Olivier Elemento, PhD, Director of the Caryl and Israel Englander Institute for Precision Medicine; Professor of Physiology and Biophysics and of Computational Genomics in Computational Biomedicine at Weill Cornell Medicine; and Associate Director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine. “The findings demonstrate that we should think about younger and older patients as having different diseases and therefore, treat them differently.”
Typically, studies of age-related differences in molecular characteristics of cancers have been conducted in one tumor type at a time, such as breast cancer, said co-first author Yajas Shah, a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences working in Dr. Elemento’s lab at Weill Cornell Medicine.
There is a strong association between aging and developing cancer. Recently, there has also been a rise in the incidence of cancer among young adults. Current estimates show that 1 in 29 males and 1 in 17 females under the age of 49 are likely to develop cancer. The most common cancers in these patients are breast, colorectal, genital tract, skin, connective tissue, and thyroid cancers.
“The insight that younger patients usually survive longer than older patients with the same cancer types inspired us to investigate age-related genetic differences in tumors,” said co-first author Akanksha Verma, PhD, of Dr. Elemento’s lab at Weill Cornell Medicine.
Study Details
For their study, the investigators examined differences in tumor types by age using The Cancer Genome Atlas, a large databank of genomic and gene expression data of primary cancer tumors and matched healthy tissue samples across 33 cancer types. They identified 16 cancer types with significant differences in overall survival between younger and older patients. Next, they narrowed the list to six with the most marked differences in gene expression between younger and older patients: breast, uterine, ovarian, thyroid, and lung cancers, and gliomas. Age ranges for younger and older patients varied by tumor type, with the younger group defined as the youngest 25% and the oldest defined as the oldest 25% for each cancer type.
The researchers found that tumors from younger patients showed advanced signs of aging. For example, they discovered younger patients’ tumors had biologic ages older than the chronologil age of matched noncancerous tissue as measured by tags, called DNA methylation marks. These marks alter gene expression and vary with age. In addition, tumors from younger patients also contained a higher number of cells that have stopped dividing but have not died, known as senescent cells, compared with tumors from older patients. Senescent cells are associated with aging and inflammation and may play a role in cancer development.
Compared with tumors from older patients, younger patients’ tumors also had more mutations associated with aggressive disease and contained more infiltrating immune cells, suggesting that younger patients mount more robust immune responses to more lethal cancers.
Potential Therapeutic Targets
Next, the researchers performed a drug survey using the Drug-Gene Interaction database to identify therapies that may better address the most frequent gene mutations observed in younger patients’ tumors and found several promising matches. For example, the poly (ADP-ribose) polymerase inhibitors olaparib and rucaparib, the mechanistic target of rapamycin inhibitor everolimus, the JAK2 inhibitor ruxolitinib, and the PD-1 immune checkpoint inhibitor pembrolizumab might be good candidates for targeted therapies for uterine cancer in younger patients.
“Overall, our study shows we should extend the concept of precision medicine to include age,” said Dr. Elemento. “We hope it may serve as a blueprint for future clinical studies stratified by age.”
Dr. Elemento is corresponding author for the Cell Reports article.
Disclosure: For full disclosures of the study authors, visit cell.com.
