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Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma

BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-re...

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Autores principales: Koh, Youngil, Kim, Hyemin, Joo, So Young, Song, Seulki, Choi, Young Hoon, Kim, Hyung Rae, Moon, Byul, Byun, Jamin, Hong, Junshik, Shin, Dong-Yeop, Park, Solip, Lee, Kwang Hyuck, Lee, Kyu Taek, Lee, Jong Kyun, Park, Daechan, Lee, Se-Hoon, Jang, Jin-Young, Lee, Hyunsook, Kim, Jung-Ae, Yoon, Sung-Soo, Park, Joo Kyung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10580633/
https://www.ncbi.nlm.nih.gov/pubmed/37848935
http://dx.doi.org/10.1186/s12967-023-04549-x
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author Koh, Youngil
Kim, Hyemin
Joo, So Young
Song, Seulki
Choi, Young Hoon
Kim, Hyung Rae
Moon, Byul
Byun, Jamin
Hong, Junshik
Shin, Dong-Yeop
Park, Solip
Lee, Kwang Hyuck
Lee, Kyu Taek
Lee, Jong Kyun
Park, Daechan
Lee, Se-Hoon
Jang, Jin-Young
Lee, Hyunsook
Kim, Jung-Ae
Yoon, Sung-Soo
Park, Joo Kyung
author_facet Koh, Youngil
Kim, Hyemin
Joo, So Young
Song, Seulki
Choi, Young Hoon
Kim, Hyung Rae
Moon, Byul
Byun, Jamin
Hong, Junshik
Shin, Dong-Yeop
Park, Solip
Lee, Kwang Hyuck
Lee, Kyu Taek
Lee, Jong Kyun
Park, Daechan
Lee, Se-Hoon
Jang, Jin-Young
Lee, Hyunsook
Kim, Jung-Ae
Yoon, Sung-Soo
Park, Joo Kyung
author_sort Koh, Youngil
collection PubMed
description BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and Kras(G12D) mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log(2) OR = 1.65, P = 3.08 × 10(–3)). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67(+) cells increased significantly in pancreatic organoids derived from Galc knockout Kras(G12D) mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04549-x.
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spelling pubmed-105806332023-10-18 Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma Koh, Youngil Kim, Hyemin Joo, So Young Song, Seulki Choi, Young Hoon Kim, Hyung Rae Moon, Byul Byun, Jamin Hong, Junshik Shin, Dong-Yeop Park, Solip Lee, Kwang Hyuck Lee, Kyu Taek Lee, Jong Kyun Park, Daechan Lee, Se-Hoon Jang, Jin-Young Lee, Hyunsook Kim, Jung-Ae Yoon, Sung-Soo Park, Joo Kyung J Transl Med Research BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and Kras(G12D) mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log(2) OR = 1.65, P = 3.08 × 10(–3)). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67(+) cells increased significantly in pancreatic organoids derived from Galc knockout Kras(G12D) mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04549-x. BioMed Central 2023-10-17 /pmc/articles/PMC10580633/ /pubmed/37848935 http://dx.doi.org/10.1186/s12967-023-04549-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Koh, Youngil
Kim, Hyemin
Joo, So Young
Song, Seulki
Choi, Young Hoon
Kim, Hyung Rae
Moon, Byul
Byun, Jamin
Hong, Junshik
Shin, Dong-Yeop
Park, Solip
Lee, Kwang Hyuck
Lee, Kyu Taek
Lee, Jong Kyun
Park, Daechan
Lee, Se-Hoon
Jang, Jin-Young
Lee, Hyunsook
Kim, Jung-Ae
Yoon, Sung-Soo
Park, Joo Kyung
Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma
title Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma
title_full Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma
title_fullStr Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma
title_full_unstemmed Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma
title_short Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma
title_sort genetic assessment of pathogenic germline alterations in lysosomal genes among asian patients with pancreatic ductal adenocarcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10580633/
https://www.ncbi.nlm.nih.gov/pubmed/37848935
http://dx.doi.org/10.1186/s12967-023-04549-x
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