Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer

Abstract

Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.

Whole genome sequencing identifies rare genetic variants in familial pancreatic cancer patients

“…The genetic diversity of FPC patients was observed not only across samples in our cohort, but also within individual FPC patients showing intraindividual allelic heterogeneity (multiple PTVs of the same gene in the same patient) and locus heterogeneity (multiple PTV genes in the same patient). High genetic heterogeneity of FPC patients has been reported by previous sequencing studies in cohorts from the United States and Germany (Roberts et al, 2016;Slater et al, 2021). Our results provide new evidence reconfirming FPC as a genetically heterogeneous disease associated with rare germline variants.…”

“…explain less than 20% of FPC cases leaving the genetic basis of more than 80% of FPC patients unknown (Roberts et al., 2016). A very recent WGS study on FPC patients failed to detect pathogenic variants in BRCA1/2 , CDKN2A , or PALB2 (Slater et al., 2021). Likewise, association testing of our recent WGS on first‐degree relatives of FPC patients did not find rare variants in any of the reported FPC candidate genes (Tan et al., 2021b).…”

Protective Prognostic Biomarkers Negatively Correlated with Macrophage M2 Infiltration in Low-Grade Glioma

“…Fibroblast growth factor binding protein 3 (FGFBP3) is highly expressed in the central nervous system, which is essential for neuronal survival and differentiation in brain [26]. It affects carbohydrate and lipid metabolism [27] and was also found to have close relationships with breast cancer [28], angiogenesis [29], and familial pancreatic cancer [30]. The FGFBP3 regulates the FGF and FGFR signaling pathways.…”

Proteomics biomarker discovery for individualized prevention of familial pancreatic cancer using statistical learning

“…Research has focused on the underlying gene defects, biomarker development, and the evaluation of prospective PDAC screening programs for members of such families [ 5 ]. Current whole genome and whole exome sequencing data suggest that FPC is genetically highly heterogeneous, with no single predisposing gene responsible for the occurrence of the disease in families [ 10 , 11 ].…”