Familial Pancreatic Adenocarcinoma

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Key points

  • Familial pancreatic cancer (FPC) kindreds have 2 or more first-degree relatives ever diagnosed with pancreatic ductal adenocarcinoma.

  • Patients with FPC constitute 8% to 10% of all patients with pancreatic cancer. Positive family history of pancreatic cancer is a consistent risk factor, with twofold increased risk to first-degree relatives.

  • Although novel genes that predispose to FPC remain to be discovered, increased risk of pancreatic cancer is now known to be associated with half a dozen

Familial Clustering

Early reports of familial clusters of pancreatic cancer provided the first suggestion that at least a hereditary, but rare form of pancreatic cancer might exist. Reports of clusters included families in which multiple siblings were affected (but not the parents)6, 7, 8, 9 or 1 family in which 3 generations contained an affected member each.10

Familial Aggregation Studies and Analysis of Families

More formal study designs that apply epidemiologic and genetic segregation analysis methods are widely accepted standards to uncover existence of genetic

Hereditary Syndromes with Increased Risk of Pancreatic Cancer

In 1996, Lynch and colleagues31 asserted that genetic factors were estimated to play a significant role in 5% of the total pancreatic cancer burden. Much research has been accomplished in the intervening time. Although novel genes that predispose to FPC remain to be discovered, increased risk of pancreatic cancer is now known to be associated with half a dozen inherited syndromes with known germline mutations, including BRCA1, BRCA2, CDKN2A, PALB2, ATM, mismatch repair genes, and PRSS1 and

Clinical translation of familial pancreatic cancer research

As with other cancer genes, the transfer of discoveries to the clinical laboratory and bedside is occurring rapidly. Regrettably, there still remain gaps in knowledge so that strategies cannot be fully shaped to guide patients and their families. Multiple fronts have been opened: personalized therapy, risk assessment and genetic testing, as well as screening and surveillance.

Summary

FPC kindreds contain at least 2 first-degree relatives with pancreatic ductal adenocarcinoma. Genetic studies of FPC have uncovered important new genes and insights about the genetics of pancreatic cancer. Over a decade of research reveals that a half dozen known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the most prominent of which are BRCA2 and CDKN2A. Next-generation sequencing technologies successfully identified new FPC genes, PALB2

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    Disclosures: The author has no conflicts.

    Supported in part by National Cancer Institute grants R01 CA97075 and P50 CA102701.

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