Researchers from Johns Hopkins and other institutions
have developed a new prediction model for genetic defects
known as Lynch syndrome, which predisposes families to
develop colorectal cancer. The model, called MMRpro, is
based on an individual's detailed family history of
colorectal and endometrial cancer, as well as on knowledge
of how genetic mutations manifest themselves, in the form
of tumors. It can assess a person's probability of carrying
a particular defect within so-called mismatch repair genes.
The study is published in the Sept. 27 issue of the
Journal of the American Medical Association.
Sining Chen, lead author of the study and an assistant
professor in the Johns Hopkins
Bloomberg School of
Public Health's
Department of Environmental Health Sciences, said,
"Genetic defects can be passed from parents to their
children. As a result, colon cancer runs in families. Our
model will help identify individuals likely to have
particular genetic defects. The results will give them
useful information about their colon cancer risk before
they decide whether to undergo invasive screenings or
expensive genetic testing."
Lynch syndrome, also known as hereditary nonpolyposis
colorectal cancer, is characterized by the inheritance of
defects in the MLH1, MSH2 and MSH6 genes. These three
genes--known as mismatch repair, or MMR, genes--help repair
mismatches that can occur during the duplication of the
genetic code when new cells are made. Of the projected
600,000 carriers of MMR mutations in the United States,
each has approximately a 50 percent chance of being
diagnosed with colorectal cancer by age 70; women also have
a 50 percent chance of developing endometrial cancer,
according to Giovanni Parmigiani, senior author of the
study and a professor of oncology, biostatistics and
pathology at Johns Hopkins.
The researchers applied MMRpro software to 279
individuals' family histories. The study participants were
tested with sensitive laboratory mutation-detection
techniques. MMRpro predictions were compared to the
laboratory test results, as well as to predictions made
with widely used assessment guidelines.
The researchers found that MMRpro predicted mutation
carriers more accurately than two other assessment
tools--the Bethesda guidelines and the Amsterdam
criteria--that are currently available to families faced
with the possibility that they have inherited the genetic
defects related to colon cancer. MMRpro can identify more
mutation carriers and fewer noncarriers than other
assessment tools. MMRpro was able to assess individuals who
do not have cancer as well as those who already do;
existing assessment tools can be applied only to
individuals with cancer. In addition, certain MMR genetic
mutations are hard to detect in laboratory tests; MMRpro
was able to provide a useful risk assessment when
conventional laboratory tests did not find a genetic
mutation.
"Colorectal cancer is the second-largest cause of
cancer deaths in the U.S. It is also one of the most
preventable forms of cancer. We expect that MMRpro will
contribute significantly to controlling the disease by
prioritizing high-risk individuals for intensive screening
and early detection," Chen said. "We also expect that it
will be a tool for investigators interested in
understanding inherited colorectal cancer, allowing them to
select families to more efficiently study these genetic
defects."
The study authors warn that MMRpro results should be
interpreted by physicians and cancer counselors. The model
software is available at
astor.som.jhmi.edu/BayesMendel and at
www8.utsouthwestern.edu/utsw/cda/dept47829/files/
65844.html.
The study was written by Chen, Wenyi Wang, Parmigiani,
Kenneth W. Kinzler, Francis M. Giardiello and Kathy Romans
at Johns Hopkins. Additional co-authors are Shing Lee,
Khedoudja Nafa, Johanna Lee, Patrice Watson, Stephen B.
Gruber, David Euhus, Jeremy Jass, Steven Gallinger,
Noralane Lindor, Graham Casey, Nathan Ellis, the Colon
Cancer Family Registry and Kenneth Offit.
Funding was provided by grants from the Specialized
Program of Research Excellence in Gastrointestinal Cancer
at the Johns Hopkins Medical Institutions, the National
Cancer Institute, the Cancer Research and Prevention
Foundation, the John G. Rangos Sr. Family Charitable
Foundation, the Clayton Fund, the
Niehaus-Southworth-Weissenbach Research Fund and the Evan
Frankel Fellowship.