Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene

Abstract

There is considerable debate about the value of personal genome sequencing (1). In addition to the five individuals whose genomes have been sequenced in their entirety, 68 patients have been evaluated for tumor-specific mutations in all exons of protein coding genes (exomic sequencing). This coincidentally yielded information about germline sequence variations in these individuals (2-4). To explore the utility of such information, we evaluated a pancreatic cancer patient (Pa10) whose tumor DNA had been sequenced in (4). This patient had familial pancreatic cancer, as defined by the fact that his sister also had developed the disease.Among the 20, 661 coding genes analyzed, we identified 15,461 germline variants in Pa10 not found in the reference human genome. Of these, 7318 were synonymous, 7721 were missense, 64 were nonsense, 108 were at splice sites, and 250 were small deletions or insertions (54% in-frame). Past studies have shown that tumors arising in patients with a hereditary predisposition harbor no normal alleles of the responsible gene: one allele is inherited in mutant form, often producing a stop codon, and the other (wild type) allele is inactivated by somatic mutation during tumorigenesis. In Pa10, only three genes met these criteria: SERPINB12, RAGE and PALB2. Of these, we considered PALB2 to be the best candidate because germline stop codons in SERPINB12 and RAGE, but not in PALB2, are relatively common in healthy individuals and because germline PALB2 mutations have previously been associated with breast cancer predisposition and Fanconi anemia(5) although its function is not well understood. Pa10 harbored a germline deletion of 4 bp (TTGT at c.172-175) producing a frameshift at codon 58; the pancreatic cancer that developed in Pa10 had somatically acquired a transition mutation (C to T) at a canonical splice site for exon 10 (IVS10+2).To determine whether PALB2 mutations occur in other patients with familial pancreatic cancer, we sequenced this gene in a cohort of 96 familial pancreatic cancer patients, 90 of which were of Caucasian ancestry. Sixteen of these patients had one first degree relative with pancreatic cancer and 80 had at least two additional relatives, at least one of which was first degree, with the disease. Truncating mutations were identified in three of the 96 patients, each producing a different stop codon (Fig. 1). 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. We determined the germ-line sequence of an affected brother in one of these kindreds, and he harbored the same stop codon. Truncating mutations in PALB2 are rare in individuals without cancer; none have been reported among 1,084 normal individuals in a previous study using a cohort of similar ethnicity to ours (6). While some families we identified with a PALB2 stop mutation had a history of both breast and pancreatic cancer, breast cancer

Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated

“…Our results are in line with the results of these previous reports in which no PALB2 mutations, 9,14 or low prevalence of PALB2 mutations, 2,4,[7][8]10 were found. It should be mentioned that the relatively small sample size could be a possible explanation for that no mutation carrier was identified in the current study.…”

“…2 Mutations in this gene may be associated with familial clustering of PC and BC. [1][2][3][4][5][6][7][8][9][10] Previous studies have shown that PALB2-mutation-positive familial BC (FBC) patients were significantly more likely to have a relative with PC, 5 and that nearly all PALB2-mutation positive familial PC (FPC) families were affected by at least one BC case. 4 Given these findings and the fact that the prevalence of gene mutations varies between different populations, we aimed to determine the prevalence of PALB2 mutations in Dutch cohorts of non-BRCA1/2 FPC patients and of non-BRCA1/2 FBC patients with a personal or family history of PC.…”

Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing

“…It is known that a common feature of all ORPs is the conserved C-terminal ORD. 30,31 Tong et al 32 proved that the unifying role in all ORP homologs was the binding of PI [4]P to ORD, with additional sterol binding for certain homologs, and yeast complementation tests showed that PI [4]P binding to ORD is essential for function. A strictly conserved OSBP-fingerprint motif, "EQVSHHPP, " in the ORD region of OSBPL2 is a specific binding motif for the head of the group of the PI[4]P ligand, suggesting roles as phosphoinositide-binding proteins [20][21][22] (Figure 2e).…”

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] It is estimated that more than 230 novel rare disease genes have been discovered to date using WES. 11 Several new NSHLcausative genes have also recently been revealed via WES, including GPSM2, DNMT1, BDP1, ELMOD3, TNC, GRXCR2, and ADCY1.…”

Early diagnosis of pancreatic cancer: Current trends and concerns

“…It has been reported that BRCA2, PALB2, and ataxia telangiectasia mutated germ‐line mutations are most frequently identified in familial PC cases 32, 33, 34. In July 2013 in Japan, JPS established the familial PC registry for early diagnosis, and already started this registry in 2015.…”