Pancreatic cancer is relatively uncommon. According to the latest GLOBOCAN report, over half a million cases were reported in 2022, which represents 2.6% of all reported cancers. Similarly, there were 467,000 related deaths which accounted for less than 5% of cancer-related mortality [1–3]. Despite the advances in the detection and management of pancreatic cancer, prognosis remains dismal. With a 5-year survival rate of less than 10%, it is considered among the worst human malignancies [4, 5].

Approximately 95% of pancreatic neoplasms are ductal adenocarcinomas (PDAC), which are associated with the worst prognosis. Multiple risk factors have been identified in patients with pancreatic cancer; cigarette smoking and family history are dominant ones [6]. Several studies have demonstrated that family history of pancreatic cancer in a first degree relative is associated with a 2- to 3-fold increased risk of pancreatic cancer [7]. Familial pancreatic cancer (FPC), which accounts for approximately 5–10% of all PDAC, is defined as kindreds with two or more affected first-degree relatives [8, 9]. The risk of developing pancreatic cancer in these individuals is approximately 3–5 times higher compared to the general population [10, 11].

Genetic predisposition syndromes associated with pancreatic cancer account for almost 10–15% of PDAC familial cases [12–14]. The remaining 85–90% of familial cases with pancreatic cancer aggregation lack these hereditary cancer predisposition syndromes, implying that in the majority of families with PDAC susceptibility, a causative gene mutation will not be identified [15].

The most prominent hereditary cancer predisposition syndromes associated with PDAC are hereditary breast–ovarian cancer (HBOC) syndrome [16], particularly due to germline mutations in BRCA2 [17], and familial atypical multiple mole melanoma (FAMMM) syndrome due to mutations in CDKN2A [18]. Up to 17% of families of patients with pancreatic cancer could carry mutations within BRCA1 or BRCA2, even not in the context of HBOC [19]. Peutz-Jeghers syndrome (STK11) [20], Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM) [21, 22], hereditary pancreatitis (PRSS1, CFTR, CTRC, and SPINK1) [23], ataxia-telangiectasia (ATM) gene [24], and PALB2 associated pancreatic cancer [25], are inherited cancer susceptibility syndromes that have been also linked to pancreatic cancer.

Here, we describe the pattern and prevalence of germline variants among “Arab” patients with pancreatic cancer treated at a single institution.

As per the latest National Comprehensive Cancer Network (NCCN) [26] and the American College of Gastroenterology (ACG) [27] guidelines, all patients with pancreatic cancer were eligible for genetic testing regardless of their personal or family history of cancer. Patients were referred to genetic testing by their primary medical or surgical oncologists. Prior to genetic testing, patients were counseled by trained genetic counselors, and a 3-generation family history was obtained. Results of genetic testing were disclosed by the primary physicians and all patients had post-testing counseling. Peripheral blood samples were utilized for next-generation sequencing (NGS)-based multigene panel testing using either a standard 10–18 gene panel or an expanded investigational 84-gene panel. Testing was performed at a reference international genetic laboratory. Variants were classified following the American College of Medical Genetics and Genomics (ACMG/AMP) guidelines categorizing results as pathogenic/likely pathogenic (P/LP), increased-risk alleles, variants of uncertain significance (VUS), or negative [28, 29]. Cascade testing and genetic counseling were offered to patients with actionable findings.

Clinical, pathological and demographic data were obtained from our institutional-based cancer registry and from individual patient’s electronic medical records. A diagnosis of pancreatic cancer was confirmed by a pathology review at our center. Data collected at baseline including age at diagnosis, sex, tumor location and stage, Eastern Cooperative Oncology Group (ECOG) performance status, personal and family history of other cancers and treatment offered including surgery, radiotherapy and chemotherapy. Outcomes such as survival and treatment modification following genetic testing were documented.

During the study period, a total of 211 patients were enrolled, the majority (n = 195, 92.4%) were Jordanians, while the rest were non-Jordanian Arabs. All had PDAC as their first cancer upon study enrollment. The median age at diagnosis was 59 (range, 23–86) years and 133 (63.0%) were males. Most tumors (n = 121, 57.3%) involved the head or the uncinate process of the pancreas, and half (n = 107, 50.7%) had metastatic disease at presentation. Surgical resection was attempted on 73 (34.6%) patients and majority of the patients (n = 184, 87.2%) had chemotherapy, while 42 (19.9%) underwent radiation therapy (Table 1).

Patients underwent MGP testing using a standard 10 or 18-gene panel (n = 149, 70.6%) or an investigational 84-gene panel (n = 62, 29.4%). Figure 1 illustrates patients’ flow. In total, 22 (10.4%) patients had positive mutations; 14 (6.6%) as P/LP variants, while 8 others (3.8%) had increased risk allele in APC.

Most P/LP variants were in BRCA2 (n = 8), other variants identified include ATM (n = 2), CFTR, CHEK2, BRCA1, and MSH6 (one each), Fig. 2

Variants of uncertain significance were identified in 51 (24.2%) patients, Table 2.

Details of mutation variants, exon or intron involved, nucleotide and amino acid changes are illustrated in Table 3.

Though the majority (n = 173, 82.0%) had a family history of cancer in a first or second degree relative, only 41 (23.7%) were breast, ovarian or pancreatic cancers, and 5 (12.2%) of them had pathogenic variants in BRCA2 (n = 2), ATM (n = 2) and MSH6 (n = 1). Additionally, 3 (7.3%) patients had APC increased risk allele.

Age at pancreatic cancer diagnosis (≤ 50 or > 50 years), gender, disease stage at presentation (early stage versus metastatic) or tumor differentiation (well/moderately differentiated versus poorly differentiated), had no correlation with positive germline testing. However, none of 38 patients with no family history of cancer had any P/LP variants, compared to 14 (8.1%) of 173 patients with family history, p = 0.03, Table 4.

Median survival for patients with P/LP variants was 26.0 months (95% CI, 21.3–NA) compared to 13.8 months (95% CI, 12.0–17.4) for patients with negative results, p = 0.210. Patients with BRCA1 or BRCA2 had the best median survival (32.6 months), p = 0.277.

Half of patients with P/LP variants or APC increased risk allele (n = 11, 50.0%) communicated results with their relatives; 18 (69.2%) of 26 relatives who had cascade testing had positive results (APC = 6, BRCA1/2 = 5, ATM = 7).

In our study, a total of 211 patients with a confirmed diagnosis of PDAC were enrolled. Each patient underwent comprehensive genetic counseling, and those who consented had multi-gene panel testing. Our patients were recruited regardless of their family history of associated cancer. We also mandated a negative personal history of preceding malignancy. Compared to patients enrolled in other studies, our cohort may be considered at a relatively lower risk for germline mutations. In total, 14 P/LP variants were identified, most of these variants were in genes known for their association with PDAC.

None of the 38 patients who had no family history of cancer had any P/LP variants, a finding that underscores the importance of family history in identifying a subgroup of patients with PDAC who are at higher risk. A recently published study used data on 179 patients newly diagnosed with PDAC from three Spanish hospitals, regardless of their personal or family history, highlighted the importance of family history. Utilizing a 13-gene panel of genes known to be associated with PDAC, 14 (7.8%) had a P/LP variant; 6 in ATM, 6 in BRCA2, one in PALB2, and one in TP53. Patients with family history of PDAC had significantly higher odds of having a P/LP variant [OR, 3.7 (1.08–13.6)], while those with family history of breast cancer had an OR of 8.5 (2.6–26.6). Similarly, rates were higher among patients with a personal history of any other cancer [OR, 3.5 (1.1–11.5)] [30].

Age is another risk factor that may influence rates of P/LP variants. In the study cited above, none of the 51 patients over 60 years without a relevant family history of malignancies had a P/LP variant associated with PDAC. In our cohort, 51 (24.2%) were 50 years or younger, 9.8% of them had P/LP variants, compared to only 5.6% among those older than 50 years. Though the difference failed to reach statistical significance (p = 0.15), it should be an issue to be looked at in larger studies.

These findings reinforce the need for reconsideration of germline genetic testing eligibility. Current guidelines recommend testing all patients with PDAC. However, in resource-restricted setting, clinicians may concentrate on younger patients and those with personal or family history of PDCA or other cancers.

A study conducted at Mayo Clinic analyzed 302 patients with PDAC using a multigene panel comprising 25 cancer predisposition genes. This panel included 16 genes with established associations with PDAC (APC, ATM, BMPR1A, BRCA1, BRCA2, CDK4, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, SMAD4, STK11, and TP53), and nine genes without known PDAC associations (BARD1, BRIP1, CDH1, CHEK2, MUTYH, NBN, PTEN, RAD51C, and RAD51D). Of the cohort, 185 (61.3%) patients met the criteria for FPC, while the remaining 117 (38.7%) had a family history of cancer but not enough to fulfill FPC criteria. Pathogenic or likely pathogenic germline variants were identified in 11.9% of patients, involving seven PDAC-associated genes (ATM, BRCA1, BRCA2, CDKN2A, MSH2, PALB2, and PMS2) and four genes not previously linked to PDAC (BARD1, CHEK2, MUTYH, and NBN). Notably, P/LP variants were detected in 14% of FPC cases and 9% of non-FPC cases, indicating a substantial prevalence of germline susceptibility variants even in patients who do not meet FPC criteria [31].

In another recent study that utilized the Dutch Nationwide Pathology Databank, 473 patients were identified with PDAC and a personal history of colorectal cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, gastric cancer, and/or melanoma. P/LP variants were identified in 75 (15.9%) patients. The most frequently altered genes were ATM (n = 22; 29.3%), CDKN2A (n = 14; 18.7%), CHEK2 (n = 10; 13.3%), and BRCA2 (n = 10; 13.3%). These 4 genes collectively accounted for almost 75% of the whole cohort [32].

Our rate of P/LP variants is lower than those reported by Mayo Clinic, the Spanish and the Dutch studies. Such lower rate can be explained by the fact that we included all pancreatic cancer patients regardless of their age or family history. Additionally, the Mayo cohort included a significantly high proportion of FPC. Importantly, our findings align closely with those of Grant et al., who employed a 13-gene panel to assess 290 unselected PDAC patients. Their study identified P/LP variants in only 11 individuals (3.8%), underscoring a similarly low mutation prevalence. This reduced yield is plausibly linked to the lower-risk profile of the cohort, with merely one-third reporting a family history of pancreatic, breast, or ovarian malignancies [33].

Sharing test results with family relatives and subsequent cascade testing is extremely important but unfortunately uptake was lower than anticipated. Only half of our patients communicated positive test results, a rate that can be increased with appropriate education and awareness.

Our study, while valuable in its insights, is not without limitations. The cohort was predominantly Jordanian, which may limit generalizability to more diverse Arab populations. The sample size of patients with P/LP variants was relatively small, limiting the power of subgroup analyses. Additionally, genetic testing varied between patients, with some using an expanded panel, potentially leading to inconsistent mutation detection. Finally, although survival differences were observed between mutation-positive and mutation-negative groups, they were not statistically significant, possibly due to sample size or follow-up limitations.

This study highlights the prevalence and clinical relevance of germline mutations in Jordanian patients with pancreatic cancer, with family history emerging as a key risk factor. Despite the relatively low mutation rate and limited uptake of cascade testing, the findings underscore the importance of tailored genetic screening, guided by age and family history, particularly in resource-limited settings. Such an approach may enhance detection, improve counseling, and optimize familial risk assessment.

Prior Presentation: Data was presented, in part, as a poster presentation (poster number:736) at the GI ESMO annual conference in Munich, Germany 26–29 June 2024.