Familial pancreatic cancer (FPC) is defined as a family with at least two first-degree relatives (FDRs), meaning a parent-child or sibling pair, with PC without an identifiable syndrome or genetic cause within the family [5]. Relatives are stratified dependent on relationships to the affected relatives; an individual with three or more FDR with PC in a family meeting the FPC definition carries a 17 relative risk (RR) [5]. PC risk is estimated to be 6.4-fold greater in individuals with two FDRs with PC (lifetime risk 8–12%) and 32-fold greater in individuals with three or more FDRs with PC (lifetime risk 40%) [6]. Among kindreds with familial PC, risk is higher in those with a young-onset PC (age <50 years, RR, 9.3) compared with those without [7]. A 2009 meta-analysis demonstrated that having just one affected relative resulted in an 80% increased relative risk of developing PC [3]. Still, there is no consensus on whether to screen individuals without an affected FDR, including individuals with a young-onset PC relative or patients with new-onset diabetes [2]. Nevertheless, recognition of individuals at increased risk of having genetic mutations may aid in defining patients that will benefit from early detection of these pancreatic neoplasms, as well as targeted, gene-specific therapy [3].

Familial pancreatic cancer (FPC) is responsible for approximately 80% of PC with a genetic basis [3]. Among FPC kindreds, having two or three FDRs with PC was associated with a 6.4-fold and 32-fold greater risk of developing PC, respectively [3]. Additionally, studies of the European Registry of Hereditary Pancreatitis and FPC as well as the German national case collection for FPC registries have described anticipation, meaning developing PC roughly 10 years earlier than their affected parent, in 59–80% of over 100 FPC families [3]. Segregation analyses have shown evidence for a yet unidentified autosomal-dominant, high-risk allele influencing PC onset age present in 7 of 1000 individuals [3]. The palladin gene, a proto-oncogene overexpressed in some sporadic pancreatic tumors, has been found to be mutated in affected members of one PC family [3]. This gene codes for a cytoskeleton protein that promotes tumor invasion in fibroblasts [3]. The occurrence of multiple primary malignancies in FPC kindreds suggests an underlying genetic predisposition, with variable penetrance, interaction with other modifier alleles, and gene-environment factors [4].

Hereditary pancreatitis (HP) is rare but is the only known inherited cancer predisposition syndrome for which PC is the sole cancer risk factor [5]. Hereditary pancreatic cancer is defined as a genetic syndrome with an identifiable gene mutation associated with an increased PC [5]. HP is an inherited form of chronic pancreatitis, where a subset of families carry gain-of-function mutations in PRSS1, which codes for a cationic trypsinogen digestive enzyme, with a penetrance estimated at 80% [5]. The SPINK1 gene codes for a serine protease inhibitor that inhibits active trypsin; mutations in this gene also have associations with various forms of pancreatic disease, including pancreatitis [3]. Typically, HP is characterized by recurrent attacks of acute pancreatitis starting in the first to second decade of life and can lead to pancreatic failure, diabetes, and PC risk ranging from 18% to 53% [3, 5, 8]. A 2010 meta-analysis found a relative risk of 69 for PC for patients with HP compared to the general population [3]. PC surveillance is challenging in HP patients as there is gross distortion of the pancreatic architecture by chronic pancreatitis [5]. An option for high-risk patients is total pancreatectomy, with or without islet autotransplantation (TPIAT) [5]. There is an increased risk in patients who smoke and have diabetes [5]. Some large HP families have never had a case of PC, and caution is required prior to recommending surgery [5].

Homozygous mutations in the autosomal recessive CFTR gene cause cystic fibrosis, which is associated with both a younger age of onset (median age of 35) and 5.3-fold increased risk of PC development [3]. However, even when a CFTR gene mutation is inherited in heterozygous fashion, a fourfold greater chance of developing chronic pancreatitis has been shown [3].

Germline mutations, in the BRCA2, PALB2, p16, STK11, ATM, and PRSS1 genes and the hereditary colon cancer genes, are associated with significantly increased risk of PC but explain only approximately 10% of the familial susceptibility to PC [2]. Individuals with PC susceptibility gene mutations may not have many affected family members; thus, patients with apparent sporadic PC can have BRCA2 mutations, as can those without a family history of breast or ovarian cancer [2]. Incomplete or low penetrance is a common feature of familial PC susceptibility gene mutations [2].

Patients with Peutz-Jeghers syndrome (PJS) have shown the greatest defined inherited risk factor for PC [5]. These patients present with mucocutaneous hyperpigmentation and hamartomatous polyposis who generally carry germline STK11 gene mutations have a 132-fold risk of PC with a lifetime risk at age 65–70 of 11–36% [5, 9, 10]. Diagnosis of PJS requires the presence of any one of the following:

Individuals who meet clinical criteria for PJS should undergo genetic testing for a germline mutation in the STK11 gene. Approximately 96% PJS patients have STK11 gene mutation [11]. Genetic testing in an individual who meets clinical criteria for PJS serves to confirm the diagnosis of PJS and counsel at-risk family members. However, not all mutations associated with PJS have been identified [12]. Thus, if no pathogenic STK11 mutation is found in an individual who meets clinical criteria for PJS and there is no known mutation of PJS in the family, the diagnosis of PJS is not excluded. Such individuals and their at-risk relatives still require frequent endoscopic surveillance for removal of polyps throughout the gastrointestinal tract and screening for extraintestinal cancers [12]. Otherwise, if genetic testing is performed and a mutation is found in an affected individual, then genetic testing of at-risk relatives will provide true positive or negative test results [12]. At-risk patients who receive true negative test results have a risk of cancer similar to that of the general population [12]. At-risk relatives who test positive should follow the surveillance guidelines for individuals with PJS [12].

Hereditary breast-ovarian cancer syndrome (HBOC) is an autosomal dominant disorder with increased risks for breast cancer (47–55% by age 70), ovarian cancer (17–39%), and other cancers including prostate, male breast, melanoma, and PC [5]. Cancer diagnoses present in multiple family generations often diagnosed prior to age 50, with the incidence in the general population being 1 in 500 individuals [5, 13]. Carrier frequency is increased among Ashkenazi (Eastern European) Jewish ethnicity, with 1 in 40 individuals at risk [5]. The majority of HBOC cases are due to mutations in the BRCA1 or BRCA 2 genes [5]. There are three founder mutations in this population: 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 [5]. In BRCA1 mutation carriers, there is a relative risk of 2.8% compared to the general population risk of 1.3% [14]. BRCA2 mutations have a 3.5 relative risk compared to non-mutation carriers (5–7% lifetime risk) for developing PC [5]. BRCA1 mutation carriers have a relatively small risk of PC; as such, PC surveillance does not warrant inclusion of these at-risk patients. However, with the higher risk with BRCA2, these patients warrant consideration for surveillance which will be discussed.