Inherited Gene Mutation Found to Raise Pancreatic Cancer Risk, Among Other Malignancies

An inherited gene mutation, RABL3, was identified in a highly cancer-prone family as the catalyst toward their significantly heightened risk of pancreatic cancer and other malignancies, according to a study published this week in the journal Nature Genetics.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options and an approximate familial predisposition of 10%. While some mutations have been identified to cause pancreatic, breast, and ovarian cancer, such as the gene BRCA2, in most cases the causative genetic flaw is unknown.

Scientists from Dana-Farber/Brigham and Women’s Cancer Center conducted a whole-genome sequencing (WGS) and analysis on a cancer-prone family with 5 cases of pancreatic cancer and numerous cases of other cancers spanning multiple generations. Excluding for known cancer risk genes BRCA2 and p16/CDKN2A, scientists sequenced DNA of one family member diagnosed with PDAC at age 48, and that of her paternal uncle diagnosed with PDAC at age 80.

The analysis utilized a computational algorithm “based on the hypothesis that causative variants are highly penetrant and autosomal dominant, rare, and heterozygous in both affected individuals and result in protein-altering variation,” said the authors. Scientists uncovered a variant in RABL3 that causes a premature nonsense mutation at amino acid 36, which mirrored known PDAC risk genes who had an absence of protein-altering variants in their WGS. Sanger sequencing, a method of DNA sequencing, similarly showed significant co-segregation of the mutated RABL3 allele with cancer among other available family members.

The RABL3 mutation was found to accelerate the movement of a known pancreatic cancer protein, KRAS, within the cell. This alteration initiated the placement of KRAS in the cell membrane and subsequently promoted cancerous growth.

As the Exome Aggregation Consortium (ExAC) database contained only one other occurrence of RABL3, scientists needed to conduct research in vivo to confirm their findings:

• Zebrafish ortholog, Rabl3, highly conserved with 100% identity through the first 50 amino acids, including position 36 where human familial nonsense mutation occurs
• Scientists recapitulated the mutation in zebrafish through CRISPRCas9 genome editing, resulting in mutant alleles that encode a premature protein truncation (mutant labeled as Rabl3-TR)
• Impact of the alleles on cancer was examined in two independent tumor models that utilized either genetic predisposition or chemical carcinogenesis

Both approaches revealed that mutant Rabl3-TR zebrafish develop cancers at statistically significant rates, and with greater frequency than their non-mutated counterparts.

Lead study author Sahar Nissim, MD, PhD, a cancer geneticist and gastroenterologist at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, emphasized the importance of early PDAC detection and further research studies. “There is evidence that catching pancreatic cancer through screening of high-risk individuals may improve outcomes,” said Nissim. “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.”

While the mutation is very rare, screening for its existence remains vital due to its distinction as a hereditary pancreatic cancer. “We anticipate that testing for this genetic mutation will be recommended in any individual with a strong family history of pancreatic cancer,” said Nissim.

Reference

Nissim S, Leshchiner I, Mancias JD, et al. Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. [published online August 12, 2019]. Nature Genetics. doi: 10.1038/s41588-019-0475-y.