Inherited pancreatic cancer risk mutation identified

  • Scientists have found
    a rare, inherited gene mutation that raises the risk of pancreatic cancer and
    other malignancies
  • In the future,
    individuals with a strong family history of pancreatic cancer could be tested
    to determine if they carry the mutation.

Scientists studying a highly cancer-prone
family have identified a rare, inherited gene mutation that dramatically raises
the lifetime risk of pancreatic and other cancers.

The discovery of the previously unknown
mutation, reported in Nature
Genetics
 by investigators
from Dana-Farber/Brigham
and Women’s Cancer Center
, could lead to routine testing of individuals with a strong
family history of pancreatic cancer to determine if they carry the mutation,
occurring in the gene known as RABL3. If so, they could be screened to detect
pancreatic cancer in an earlier, potentially more treatable stage. “There is
evidence that catching pancreatic cancer through screening of high-risk
individuals may improve outcomes,” said Sahar Nissim, MD, PhD, a cancer geneticist and
gastroenterologist at Dana-Farber Cancer Institute and Brigham and Women’s
Hospital, and first author of the study.  In addition, their relatives
could choose to be tested to learn if they carry the mutation. Senior author of
the report is Wolfram Goessling, MD, PhD, Chief of Gastroenterology at the
Massachusetts General Hospital.

About 10 percent of pancreatic cancers have a
familial pattern, and in most cases the causative genetic flaw isn’t known,
although some mutations have been identified. One inherited mutation that can
predispose individuals to pancreatic cancer occurs in the gene BRCA2, the gene
also known to cause some breast and ovarian cancers. The newly identified
mutation in the gene RABL3 similarly increases the likelihood that cancer will
develop during the person’s lifetime.

“Pancreatic cancer is a challenging disease
with limited treatment options,” the investigators said. “Familial pancreatic
cancer, in which an inherited genetic mutation is responsible for multiple
cases in a single family, may give us precious insights that open new
preventative and treatment options for pancreatic cancer.”

The RABL3 mutation was pinpointed when
scientists studied a family in which there were five relatives with pancreatic
cancer and multiple family members with other cancers – a pattern suggesting an
inherited mutation causing predisposition to developing cancer. The analysis
included sequencing the DNA of one family member, who developed pancreatic
cancer at age 48, and that of her paternal uncle, who was diagnosed with it at
age 80. The RABL3 mutation was also found in several other family members who
developed cancer and in one family member who has not been diagnosed with
cancer.

Confirming that a new genetic mutation
causes cancer by epidemiological approaches often requires many years of
searching for similar families around the world. Therefore, the scientists
turned to the zebrafish model. By recapitulating the genetic mutation in large
zebrafish populations, the team could perform rapid epidemiological studies in
this animal model to assess the impact of the mutation on cancer risk. Indeed,
similar to individuals in the patient family, zebrafish carrying the RABL3
mutation had dramatically higher rates of cancer.

In contrast to “somatic” genetic mutations
that occur during a lifetime and can cause cells to turn malignant, the
mutation in RABL3 is a cancer susceptibility gene mutation that an individual
is born with and that increases the risk of cancer developing later in life.
Specifically, the researchers said the RABL3 mutation accelerates the movement
of a known pancreatic cancer protein, KRAS, within the cell. This alteration
facilitates the placement of KRAS in the cell membrane and triggers a series of
events that promote cancerous growth. Because KRAS activity is altered in a
majority of pancreatic cancers, continued study of the RABL3 mutation’s impact
on KRAS activity could provide important insights about pancreatic cancer
development as well as a new strategy for targeted therapy, said the
scientists. “This work highlights the power of studying and understanding rare
family syndromes: from just one family, we have uncovered broadly important
insights into pancreatic cancer and how we may better prevent or treat it,” Dr.
Nissim said.

The researchers emphasized that the RABL3
mutation is rare in the general population but said that testing for it – and
potentially other mutations in the RABL3 gene – may reveal the genetic
predisposition in other families with an unsolved hereditary cancer syndrome.
Identifying a mutation in these families would help guide which relatives
should consider pancreatic cancer screening.

“While testing for this specific genetic
mutation is not available on current commercial genetic testing panels, we
anticipate that the commercial tests will incorporate mutations in this gene in
future panels,” said Nissim, who is a physician in Dana-Farber’s Cancer
Genetics and Prevention Center. “We anticipate that testing for this genetic
mutation will be recommended in any individual with a strong family history of
pancreatic cancer.”

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