How genes and environmental forces raise cancer risk
[ Fall 2008 ]
Monica Ter-Minassian is scouring the genome for time bombs. Using gene-reading technology and analytic techniques, this Harvard School of Public Health doctoral student is on the hunt for subtle variations in human DNA that might help identify the causes of rare neuroendocrine and esophageal tumors, or provide a deeper understanding of why smoking provokes lung cancer in some people but not in others.
Like most complex diseases, cancer results not from a single flawed gene, but rather the interplay of multiple genes and any accumulated damage to DNA caused by environmental factors such as exposure to chemicals, or aspects of lifestyle, such as smoking. To gain a better picture of this recipe for human disease, HSPH recently launched the Genes and Environment Initiative, pulling together students and faculty trained in environmental health, population science, biostatistics, and basic biological science.
Few scientists are fully grounded in so many areas. But Ter-Minassian came to HSPH with a range of expertise developed as a researcher in the genetic epidemiology branch of the National Cancer Institute (NCI) from 2002 to 2004. Previously she worked as a genetic counseling intern in Boston-area hospitals, gaining an appreciation, she says, of the need to help patients understand the interplay between their DNA and external forces that influence their risks for disease. Now, based in the School’s Department of Environmental Health, she analyzes populations for genetic factors that raise or lower cancer risk.
“Cancer researchers must understand how genes are expressed and interact with environmental toxins or nutrients at different points in tumor development. A strong biology and genetics background helps,” says Ter-Minassian, whose talent earned her a prestigious Taplin Fellowship for 2007 and 2008.
“It’s hard to find people with Monica’s mix of skills,” says her advisor, Professor of Occupational Medicine and Epidemiology David Christiani, who has taught at HSPH for more than 20 years. “In the field of gene-environment interactions, she’s one of the most capable people I’ve ever met.”
MINING THE SNPS
Ter-Minassian is analyzing common variations in four genes linked to lung cancer, exploring how these subtle points of difference may be modified by age, gender, and smoking status. These variants, known as SNPs (“snips,” short for single nucleotide polymorphisms), occur all along the chromosomes without affecting gene function. Because they lie nestled within functional stretches of DNA representing as-yet-unidentified genes, scientists searching for new genes related to a particular disease like to start by comparing SNPs of people with and without that disease.
After mining online catalogs of SNPs compiled by many scientists, Ter-Minassian, with the Christiani team, chose 1,536 candidate SNPs from genes already linked to lung cancer. A lab tested for their presence in DNA from study subjects at the Massachusetts General Hospital, in Boston. Now Ter-Minassian is searching for SNP patterns that go hand in hand with a confirmed lung cancer diagnosis.
In a second study, Ter-Minassian took a closer look at a subset of four SNPs. “We did see some interesting results in one particular SNP in a gene called FASLG,” Ter-Minassian says. “We looked at different subgroups of patients, and the strongest evidence showed this FASLG SNP poses the greatest risk for younger people.” The biological reason, she says, is that expression of this SNP’s gene decreases in people over 60.
Ter-Minassian is also exploring possible genetic roots of susceptibility to esophageal adenocarcinoma, for which smoking is a known risk, and neuroendocrine cancers, which have no known environmental factors. She hopes to identify SNPs that not only point to cancer susceptibility, but also hint at patients’ survival times. This is particularly important for esophageal cancer patients, at least one-third of whom die within a year.
POTENTIAL FOR NEW TREATMENTS
Ter-Minassian is still relatively new to these sorts of population-based studies, but her interest goes back to her undergraduate years at the Massachusetts Institute of Technology. “My senior thesis was on bacterial genetics, but I was fascinated with a course in human genetics, where we had an almost ‘grand rounds’ experience of case studies, meeting patients with inherited diseases like Duchenne’s muscular dystrophy and Huntington’s disease,” she says.
It was while studying genetic diseases in families at NCI that Ter-Minassian first began wondering about the role of environmental factors, such as sunlight exposure in familial melanomas in Italy, or alcohol and spicy food consumption in esophageal cancers in north-central China. Since then, she has seen a “dramatic shift” in the way people think about disease susceptibility. “Instead of focusing on inherited gene mutations,” she says, “researchers now consider a mix of genetic and environmental effects.” Inspired, Ter-Minassian sees real potential for research on cancer susceptibility and survival to lead to better patient treatments.
“There is still a lot we don’t know about complex diseases like cancer, where the mode of inheritance is not clear,” says this multi-faceted scientist, who plans to graduate next year. “There’s definitely a lot to be done.”
Amy Roeder is the Development Communications Coordinator in the Office for Resource Development.
Originally published in Fall 2008