Pancreatic Cancer, Susceptibility To, 3

A number sign (#) is used with this entry because heterozygous mutation in the PALB2 gene (610355) on chromosome 16p12 confers susceptibility to pancreatic cancer.

For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see 260350.

To explore the utility of personal genome sequencing, Jones et al. (2009) screened 20,661 coding genes for germline mutations in a patient with pancreatic cancer whose tumor DNA had previously been sequenced. They detected 15,461 germline variants. Three genes, including PALB2, carried variants in both germline and tumor DNA. PALB2 was considered the best candidate for a pancreatic cancer susceptibility gene because of the rarity of terminating PALB2 mutations in healthy individuals and because PALB2 had previously been implicated in breast cancer and Fanconi anemia. This patient harbored a germline deletion of 4 basepairs that resulted in a frameshift (610355.0007). Jones et al. (2009) also identified truncating mutations in 3 of 96 patients with familial pancreatic cancer (e.g., 610355.0008). The average age of onset of pancreatic cancer in these families was 66.7 years, similar to the mean age of onset of 65.3 years in the families without PALB2 mutations. Truncating mutations in PALB2 are rare in individuals without cancer; none were reported among 1,084 normal participants in a previous study that used a cohort of similar ethnicity (primarily Caucasian) (Rahman et al., 2007). Although some families that Jones et al. (2009) identified with a PALB2 stop mutation had a history of both breast and pancreatic cancer, breast cancer was not observed in all families. Jones et al. (2009) concluded that PALB2 appears to be the second most commonly mutated gene for hereditary pancreatic cancer. The most commonly mutated gene is BRCA2 (600185), whose protein product is a binding partner for the PALB2 protein.

Zhen et al. (2015) tested germline DNA from 727 unrelated probands with pancreatic cancer and a positive family history for mutations in BRCA1 (113705) and BRCA2 (including deletions and rearrangements), PALB2, and CDKN2A (600160). Among these probands, 521 met criteria for familial pancreatic cancer (FPC; at least 2 affected first-degree relatives). The prevalence of deleterious mutations, excluding variants of unknown significance, among FPC probands was BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carried more mutations in the 4 genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%; OR = 2.40, 95% CI 1.06-5.44, p = 0.03). The probability of testing positive for deleterious mutations in any of the 4 genes ranged up to 10.4%, depending on family history of cancers.