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Germline RABL3 Mutation May Increase Risk of Pancreatic Cancer Development

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Key Points

  • 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 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.
  • Similarly to individuals in the cancer-prone family, zebrafish carrying the RABL3 mutation had higher rates of cancer.
  • The RABL3 mutation accelerates the movement of a known pancreatic cancer protein, KRAS, within the cell.

Scientists who studied a highly cancer-prone single family have identified a rare, inherited gene mutation that may raise the lifetime risk of pancreatic and other cancers. Their findings were published by Nissim et al in Nature Genetics.

The discovery of the previously unknown mutation could lead to routine testing of individuals with a strong family history of pancreatic cancer to determine if they carry a mutation occurring in the gene RABL3. If so, they could be screened to detect pancreatic cancer in an earlier, potentially more treatable stage. In addition, their relatives could choose to be tested to learn if they carry the mutation.

“There is evidence that catching pancreatic cancer through screening of high-risk individuals may improve outcomes,” said first study author Sahar Nissim, MD, PhD, a cancer geneticist and gastroenterologist at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.  

About 10% 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 BRCA2.

“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 preventive and treatment options for pancreatic cancer.”

Familial and Additional Analyses

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 pancreatic cancer 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 epidemiologic 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 epidemiologic studies in this animal model to assess the impact of the mutation on cancer risk. Similarly to individuals in the cancer-prone family, zebrafish carrying the RABL3 mutation had higher rates of cancer.

Role of RABL3 and KRAS

In contrast to somatic genetic mutations that occur during a lifetime and can cause cells to turn malignant, the mutation in RABL3 is a germline cancer susceptibility gene mutation. 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,” said Dr. Nissim.

The researchers emphasized that the RABL3 mutation is rare in the general population but said that testing for it 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 Dr. Nissim. “We anticipate that testing for this genetic mutation will be recommended in any individual with a strong family history of pancreatic cancer.”

Disclosure: The research was supported by the National Institutes of Health, the National Pancreas Foundation, the Harvard Digestive Diseases Center, the Burroughs Wellcome Fund, the Pew Charitable Trusts, the Ken and Louise Goldberg Award, the Anna Fuller Fund, and the Claudia Adams Barr Program for Innovative Cancer Research. For full disclosures of the study authors, visit nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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