Pancreatic Cancer, Susceptibility To, 1

A number sign (#) is used with this entry because of evidence that the form of familial pancreatic cancer that maps to 4q32-q34 is determined by mutation in the gene encoding palladin (PALLD; 608092).

Familial pancreatic cancer (260350) occurs as part of several familial cancer syndromes and as part of hereditary pancreatitis. In addition, families with isolated pancreatic cancer have been identified, most notably the family of former President of the United States Jimmy Carter (Lynch et al., 1990; Brentnall et al., 1999; Banke et al., 2000; Hruban et al., 2001). Affected members of these families inherit pancreatic cancer in the absence of other types of cancer and in the absence of chronic pancreatitis.

A striking example of autosomal dominant pancreatic cancer is 'family X' described by Brentnall et al. (1999) and Meckler et al. (2001). The primary characteristics included early age at onset (median age 43 years) and high penetrance (more than 80%) of pancreatic cancer. Some family members developed pancreatic insufficiency before the onset of cancer.

To identify living carrier family members before the onset of cancer in family X, Brentnall et al. (1999) developed an endoscopic surveillance program that assisted in the detection of pancreatic precancerous dysplasia, also called pancreatic intraepithelial neoplasia (PanIN). PanIn, the precancerous lesion of both sporadic and familial pancreatic cancer, is graded from 1 to 3 with increasing neoplastic progression. Lesions of all 3 grades were prominent throughout the pancreatic tissue of affected family X members before cancer developed.

Eberle et al. (2002) performed a genomewide linkage screen in family X and found significant linkage (maximum lod score 4.56 in 2-point analysis and 5.36 in 3-point analysis) on chromosome 4q32-q34.

Pogue-Geile et al. (2006) attempted to identify the pancreatic cancer gene in the 4q32-q34 region by systematic sequencing of genes located there. This approach was time-consuming and ultimately unsuccessful, leading them to adopt a new strategy: looking for abnormal gene expression with a customized expression microarray for studying RNA purified from tissue samples containing the earliest stage of pancreatic intraepithelial neoplasia. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S; 608092.0001) in a highly conserved region of the gene encoding palladin (PALLD; 608092) was found in all affected family members and was absent in unaffected members of family X.

Zogopoulos et al. (2007) identified a P239S germline mutation in 1 of 84 patients with familial or early-onset pancreatic cancer and in 1 of 555 controls. The patient with the mutation was diagnosed at age 74 years, had a first-degree relative with pancreatic cancer, and another first-degree relative with melanoma. The 91-year-old control had no relatives with cancer. The authors concluded that the P239S mutation is not a common cause of familial or early-onset pancreatic cancer.