PALB2 Mutations Confer Susceptibility to Familial Pancreatic Cancer and May Provide a Novel Targeted Therapeutic Approach to Cancer

Maeve A. Lowery, MD, and Eileen M. O’Reilly, MD | August 15, 2015
Maeve A. Lowery, MD

Maeve A. Lowery, MD


Pancreatic adenocarcinoma may occur in association with several hereditary cancer predisposition syndromes. Recently, germline mutations in PALB2 have been shown to increase lifetime risk of pancreatic cancer and breast cancer, among other types. Here we review the evidence supporting PALB2, a pancreatic cancer susceptibility gene, and discuss potential implications for therapy exploiting a defective DNA damage response.

Pancreatic adenocarcinoma (PAC) is predicted to become the second-leading cause of cancer death in the United States by the year 2020, due to a rising incidence of the disease, stable-to-increasing mortality rates, and lack of progress in the development of curative therapies.1 While there are several established risk factors for development of PAC, including smoking and obesity,2,3 in the majority of cases the etiology remains unclear. In approximately 10% to 15% of patients, however, a significant family history of pancreatic cancer in two or more close relatives is apparent. Some of these cases are due to known hereditary cancer syndromes that predispose to PAC, the most common of which are germline mutations in BRCA1/2, whereby the lifetime risk of PAC in a BRCA1/2 mutation carrier is estimated at between 2 to 3.5 times that of the general population.4 Less commonly known mutations including, the Li Fraumeni, Peutz Jegher, hereditary non-polyposis colon cancer (HNPCC), and familial atypical mole and melanoma syndrome (FAMMM), are known to carry an increased risk of PAC, along with the inherited conditions such as cystic fibrosis and hereditary pancreatitis (Table).5-7 In an additional group of patients with familial PAC however, a significant family history of PAC is noted, but no identifiable genetic predisposition is found. Registry studies have shown that individuals having three or more affected first-degree relatives (FDR) have a 32-fold increased risk of developing PAC, those with two affected FDRs with pancreatic cancer have a 6.4-fold increased risk, and those with a single affected FDR have a 4.5-fold increased risk. These cases are likely due to as yet unidentified genetic alterations, and family members of affected patients are optimally included in prospective registry studies.

Table 1. Hereditary Conditions Associated With Increased Risk of Pancreatic Ductal Adenocarcinoma


PALB2 mutations were first associated with PAC in 2009, when whole exome sequencing of tumor DNA from a patient with familial PAC identified a truncating mutation in PALB2. This prompted evaluation of a further 96 patients with familial PAC and confirmed an additional 3 patients also with truncating PALB2 germline mutations.8 A subsequent study of 81 European patients with familial PAC identified a truncating germline PALB2 mutation in 3 patients, all of whom had a personal history of breast and pancreatic cancer, and who had tested negative for germline mutations in BRCA1/2.9 The estimated prevalence of PALB2 mutations in patients with familial PAC from these studies of approximately 3% to 4%, however, has not been confirmed in several more recent studies of less highly selected patients.10,11 Monoallelic germline mutations in PALB2 are also associated with increased susceptibility to breast cancer12 and ovarian cancer,13 so a family history of breast or ovarian cancer is frequently noted in carriers. Biallelic germline mutation in PALB2 results in a typical Fanconi anemia phenotype, but with an additional severe predisposition to pediatric malignancies.14 Indications for germline testing for PALB2 mutations include individuals with strong family history of breast, ovarian, and pancreatic cancers who have tested negative for mutations in BRCA1/2, as well as patients with a Fanconi anemia (FA) phenotype who tested negative for other FA genes and blood relatives of individuals with a mutation in PALB2.

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TitleExpiration DateCME Credits
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment of Genitourinary CancersJul 28, 20171.5
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment of Breast CancerJul 29, 20171.5
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