Cancer Res Treat.  2023 Oct;55(4):1303-1312. 10.4143/crt.2023.291.

Prevalence and Risk Factors of Germline Pathogenic Variants in Pancreatic Ductal Adenocarcinoma

• Ryu KH
• Park S
• Chun JW
• Cho E
• Choi J
• Lee DE
• Shim H
• Kim YH
• Han SS
• Park SJ
• Woo SM
• Kong SY

• KMID: 2547804
• DOI: http://doi.org/10.4143/crt.2023.291

Abstract

Purpose
The genetic attribution for pancreatic ductal adenocarcinoma (PDAC) has been reported as 5%-10%. However, the incidence of germline pathogenic variants (PVs) in Korean PDAC patients has not been thoroughly investigated. Therefore, we studied to identify the risk factors and prevalence of PV for future treatment strategies in PDAC.
Materials and Methods
Total of 300 (155 male) patients with a median age of 65 years (range, 33 to 90 years) were enrolled in National Cancer Center in Korea. Cancer predisposition genes, clinicopathologic characteristics, and family history of cancer were analyzed.
Results
PVs were detected in 20 patients (6.7%, median age 65) in ATM (n=7, 31.8%), BRCA1 (n=3, 13.6%), BRCA2 (n=3), and RAD51D (n=3). Each one patient showed TP53, PALB2, PMS2, RAD50, MSH3, and SPINK1 PV. Among them, two likely PVs were in ATM and RAD51D, respectively. Family history of various types of cancer including pancreatic cancer (n=4) were found in 12 patients. Three patients with ATM PVs and a patient with three germline PVs (BRCA2, MSH3, and RAD51D) had first-degree relatives with pancreatic cancer. Familial pancreatic cancer history and PVs detection had a significant association (4/20, 20% vs. 16/264, 5.7%; p=0.035).
Conclusion
Our study demonstrated that germline PVs in ATM, BRCA1, BRCA2, and RAD51D are most frequent in Korean PDAC patients and it is comparable to those of different ethnic groups. Although this study did not show guidelines for germline predisposition gene testing in patients with PDAC in Korea, it would be emphasized the need for germline testing for all PDAC patients.

Keyword

Germline pathogenic variant; Pancreatic ductal adenocarcinoma; Prevalence; Risk factors

Figure

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  Fig. 1 Germline variants in patients with hereditary pancreatic cancer detected using hereditary next generation sequencing (NGS) cancer panel testing. (A) Schematic representation of the patients and study workflow. A total of 300 pancreatic cancer patients were enrolled. Patients were enrolled in the study and testing using a hereditary NGS cancer panel testing. (B) The frequency of each germline pathogenic variants. (C) One patient had three germline pathogenic variants (BRCA2, MSH3, and RAD 51D). (D) Location and number of frequent pathogenic variants in four genes (ATM, BRCA1, BRCA2, and RAD51D) associated with pancreatic cancer. Locations of frequent pathogenic variants found in patients are shown with lollipop structures. The X-axis reflects the number of amino acid residues.

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  Fig. 2 (A) Kaplan-Meier curves for progression-free survival and overall survival according to disease status and presence of pathogenic variants (PVs). The number of groups were represented as N. Median (range) survivals of progression-free survival and overall survival were as followings: resectable status (13.1 [0.7–37.3], 24.4 [0.7–75.3]) locally advanced status (13.0 [0.8–49.7], 21.4 [2.9–51.3]) and metastatic status (6.1 [0.3–53.4], 9.9 [0.3–67.2]). Germline mutations were grouped into four groups, such as PV, likely pathogenic variant (LPV), variants of uncertain significance (VUS), and not detected (ND), to determine if there was a difference in the progression-free survival and overall survival curves. It was confirmed that both progression-free survival and overall survival were not significant between the four groups. In addition, it was confirmed that there was no statistical difference in the survival curves of progression-free survival and overall survival between ND and VUS. (B) Progress of treatment and response of patients (n=20) with PVs. (C) PT002: A 51-year-old female underwent pancreatoduodenectomy had a recurrent tumor in the jejunum at the gastrojejunostomy site at 16 months. After 8 cycles of FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) treatment, the recurrent mass markedly decreased in size. After olaparib maintenance treatment, progression-free has been achieved up to 46 months with disappearance of the recurred tumor. PT168: A 65-year-old male suffered from weight loss with new-onset diabetes mellitus and was diagnosed as pancreatic cancer with multiple liver metastases. Liver biopsy confirmed moderately differentiated adenocarcinoma. After 8 cycles of FOLFORINOX treatment, pancreatic body cancer decreased in size from 27 mm to 13 mm and liver metastases were nearly invisible on follow-up computed tomography images indicating partial response. The patient received olaparib maintenance treatment, and the pancreatic body cancer further decreased in size to subcentimeter without liver metastases.

Reference

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