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Article

Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients

by
Yong-Chan Kim
1,2,
Sae-Young Won
1,2 and
Byung-Hoon Jeong
1,2,*
1
Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, Jeonbuk 54531, Korea
2
Department of Bioactive Material Sciences, Jeonbuk National University, Jeonju, Jeonbuk 54896, Korea
*
Author to whom correspondence should be addressed.
Cells 2020, 9(6), 1480; https://doi.org/10.3390/cells9061480
Submission received: 27 February 2020 / Revised: 13 June 2020 / Accepted: 15 June 2020 / Published: 17 June 2020
(This article belongs to the Special Issue Neuroregeneration in Neurodegenerative Disease)
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Abstract

:
Prion diseases are caused by misfolded prion protein (PrPSc) and are accompanied by spongiform vacuolation of brain lesions. Approximately three centuries have passed since prion diseases were first discovered around the world; however, the exact role of certain factors affecting the causative agent of prion diseases is still debatable. In recent studies, somatic mutations were assumed to be cause of several diseases. Thus, we postulated that genetically unstable cancer tissue may cause somatic mutations in the prion protein gene (PRNP), which could trigger the onset of prion diseases. To identify somatic mutations in the PRNP gene in cancer tissues, we analyzed somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database. In addition, to evaluate whether the somatic mutations in the PRNP gene in cancer patients had a damaging effect, we performed in silico analysis using PolyPhen-2, PANTHER, PROVEAN, and AMYCO. We identified a total of 48 somatic mutations in the PRNP gene, including 8 somatic mutations that are known pathogenic mutations of prion diseases. We identified significantly different distributions among the types of cancer, the mutation counts, and the ages of diagnosis between the total cancer patient population and cancer patients carrying somatic mutations in the PRNP gene. Strikingly, although invasive breast carcinoma and glioblastoma accounted for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. We suggested the possibility that somatic mutations of the PRNP gene in glioblastoma can be masked by a diagnosis of prion disease. In addition, we found four aggregation-prone somatic mutations, these being L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis of the somatic mutations in the PRNP gene in cancer patients.

1. Introduction

Prion diseases are fatal and irreversible neurodegenerative diseases caused by a deleterious form of the prion protein (PrPSc) derived from normal prion protein (PrPC) [1,2]. These diseases are accompanied by spongiform generation and astrocytosis in brain lesions. Prion diseases are the only zoonotic dementia with such a large host ranges, including scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in elk and deer, and Creutzfeldt–Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann–Sträussler–Scheinker syndrome (GSS) in humans. In CJD, there are three representative types, including sporadic CJD, familial CJD, and iatrogenic CJD [3,4,5,6,7,8,9,10,11,12].
It has been approximately three centuries since scrapie in sheep was first discovered in 1732 [5]. However, the exact roles on certain factors influencing the causative agent of the disease have not been fully explained thus far. However, in recent studies, genetic variations including somatic mutations or postzygotic mutations have been shown to cause several diseases, including neurofibromatosis, McCune–Albright disease, paroxysmal nocturnal hemoglobinuria, incontinentia pigmenti, several types of cancer, and Alzheimer’s disease [13,14,15]. In human prion diseases, point mutations in the prion protein gene (PRNP), which encodes PrP, induce familial forms of human prion diseases, including familial CJD, GSS, and FFI [6,16,17]. In addition, spontaneous de novo mutations in the PRNP gene were detected in several types of prion diseases, including sporadic CJD and GSS [18,19,20,21]. In this regard, somatic mutations in the PRNP gene can be assumed to be a cause of prion diseases. In addition, previous studies have been reported that cancer tissues showed more genetic instability and elevated expression of the PRNP gene. Thus, we postulated that cancer tissue may induce somatic mutations in the PRNP gene, which can trigger the onset of prion diseases [22,23,24,25].
To find somatic mutations in the PRNP gene in cancer tissues, we searched the information on somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database [26]. In addition, we compared the information on the somatic mutations in the PRNP gene in cancer patients with that of previously reported pathogenic mutations associated with prion diseases and with the total cancer patient population. Furthermore, to assess whether the somatic mutations in the PRNP gene in cancer patients are deleterious, we performed in silico annotation using PolyPhen-2, PANTHER, PROVEAN, and AMYCO [27,28,29,30,31,32].

2. Results

2.1. Previously Reported Prion Disease-Related Mutations

Genetic forms of human prion diseases include CJD, FFI, and GSS. Previous pathogenic mutations involved in genetic forms of prion diseases are described in Table 1. In detail, genetic CJD has been reported to carry G114V, D178N-129V, V180I, T183A, T188K, E196K, E196A, E200K, E200G, V203I, R208H, V210I, E211Q, I215V, M232R, and P238S mutations; double octapeptide deletions; and octapeptide insertions in the PRNP gene. In addition, FFI has been reported to carry D178N-129M mutations in the PRNP gene. Finally, GSS has been reported to carry P102L, P105L, P105T, P105S, A117V, G131V, Y145*, Q160*, V176G, H187R, F198S, D202N, Q212P, Q217R, Y226*, Q227*, and M232T mutations in the PRNP gene. Unique phenotypes of dementia have been reported to carry S17G, P39L, Y163*, D167N, D187fs, and R208C mutations in the PRNP gene.

2.2. 48 Somatic Mutations in the PRNP Gene in Cancer Patients

Using cBioPortal, we identified a total of 48 somatic mutations in the PRNP gene in 10,953 cancer patients. The detailed information is described in Table 2. Among the 48 mutations, 8 mutations, these being G131V, D167N, V180I, D202N, V203I, R208C, R208H, and E211Q (shaded boxes), were previously reported pathogenic mutations of prion diseases (Table 1). The locations of the identified somatic mutations are visualized in Figure 1. A total of five somatic mutations, these being M1X, G5A, L11I, W16S, and D18N, were located in the N-terminal signal peptide region. A total of five somatic mutations, including R25C, P26L, G34R, and G35A (fs), were located in the region of codons 23–51. A total of four somatic mutations, these being H61Y, Q75S (fs), H85N, and G86S, were located in an octapeptide repeat region. A total of 30 somatic mutations, these being G92E, G92X, K104E, G119R, L125F, M129T, G131V, G131R, Y145C, E146Q, R148H, R151C, M166I, D167N, N173H, H177N, V180I, E196R (FS), D202N, V203I, K204N, R208C, R208H, V209M, E211Q, C214G, Q217K, Y218C, E221G, and S230L, were located in the proteinase K resistant core region. Finally, two somatic mutations, I244F and V252L, were located in the C-terminal signal peptide region. Notably, of the 25 patients for whom we had access to cancer metastasis information, we observed no evidence of distant metastasis in 22 (92%) of them (Table 2).
In addition, we compared the information on cancer patients who carried somatic mutations of the PRNP gene with that of the total cancer patient population. The detailed information is described in Table 3. In detail, we found 48 PRNP somatic mutations carriers (subgroup 1) and 8 PRNP pathogenic somatic mutation carriers of prion disease (subgroup 2). Subgroup 1 accounts for 0.43% of the total cancer patient population assessed, while subgroup 2 accounts for 0.07% of the total cancer patient population. Subgroup 2 accounts for 17.02% of subgroup 1. The age of diagnosis in the total cancer patient population was 59.1 ± 14.5 years, in subgroup 1 was 66 ± 12.8 years, and in subgroup 2 was 66.3 ± 7.8 years. Notably, compared to the age of diagnosis in the total cancer patient population, those of subgroups 1 showed significant differences with p-values of 0.000742. In addition, there were also significant differences in the mutation count distributions between the total cancer patient population and subgroups 1 and 2, with p-values < 0.00001 and 2.3 × 10−11, respectively. Specifically, a large number of the total cancer patient population displayed mutation counts <100 (67.3%). By contrast, subgroups 1 and 2 primarily displayed mutation counts >280 (83.3% and 100%, respectively). The distribution of cancer type between the total cancer patient population and subgroup 1 showed statistical significance. (p = 6 × 10−12). Specifically, the percentage of non-small cell lung cancer patients in subgroup 1 (16.7%) was increased by 1.7-fold compared to the total cancer patient population (9.6%). The percentage of endometrial carcinoma patients in subgroup 1 (33.3%) was increased by 6.3-fold compared to the total cancer patient population (5.3%). The percentage of non-small cell lung cancer patients in subgroup 2 (12.5%) was increased by 1.3-fold compared to the total cancer patient population (9.6%). The percentage of colorectal adenocarcinoma patients in subgroup 2 (12.5%) was increased by 2.3-fold compared to the total cancer patient population (5.4%). The percentage of endometrial carcinoma patients in subgroup 2 (25.0%) was increased by 4.7-fold compared to the total cancer patient population (5.3%). Notably, although invasive breast carcinoma and glioblastoma account for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. Strikingly, distributions of six major cancer types (invasive breast cancer, non-small cell lung cancer, colorectal adenocarcinoma, glioblastoma, endometrial carcinoma, and ovarian epithelial tumor) of the patients with somatic mutations of the PRNP gene were shown to be significantly different from distributions of the six major cancer types of total patients (Figure 2).

2.3. In Silico Annotation of Mutations in the PRNP Gene

The impact of somatic mutations in PrP identified in this study and previously reported pathogenic mutations was analyzed by PolyPhen-2, PANTHER, and PROVEAN. The detailed information is described in Table 4. Notably, six somatic mutations, these being P26L, G34R, G119R, G131V, C214G, and Y218C, and five pathogenic mutations, these being P102L, P105L, G114V, H187R, and E200G were predicted to be deleterious by all three programs. We also evaluated the amyloid propensity of the mutations in the PRNP gene by AMYCO. The detailed information is described in Figure 3. Interestingly, nine mutations, these being L125F, G131V, E146Q, R151C, D167N, D178N-129M, D178N-129V, D187fs, and K204N, had an increased amyloid propensity with values of 0.23, 0.23, 0.23, 0.27, 0.27, 0.13, 0.13, 0.18, and 0.36, respectively. Among the six somatic mutations of cancer patients, four were newly identified amyloid-prone somatic mutations—L125F, E146Q, R151C, and K204N.

3. Discussion

In the present study, we identified a total of 48 somatic mutations in the PRNP gene in 10,967 cancer patients. Prion diseases are considered to be monogenic diseases, and the association of the PRNP gene with the onset of prion diseases was confirmed by genome-wide association studies (GWAS) [33,34]. Thus, the somatic mutations in the PRNP gene in cancer tissues are very important. Of the 48 somatic mutations, 8 were previously confirmed pathogenic mutations of prion diseases. Although we cited pathogenic mutations of the PRNP gene from previous studies, the penetrance on the pathogenic mutations of the PRNP gene was still debatable. In a previous study, several mutations including V180I, V210I, and M232R were found in healthy controls and these mutations showed low penetrance under 10%. Thus, these results suggest that these mutations were benign variants or low-risk variants [35]. In the present study, we further analyzed previously reported pathogenic mutations using in silico programs. Notably, V180I, V210I, and M232R mutations were predicted to be low amyloid propensity and benign by some programs (Figure 3, Table 4). Further study to confirm the deleterious effects of the mutations is needed in the future. In addition, cancer patients carrying these somatic mutations showed no evidence of distant metastasis (Table 2). Since PrP contributes to metastasis in several types of cancers, somatic mutations of the PRNP gene, which can affect normal function of PrP, may impact the property of distant metastasis [36,37]. Further validation of distant metastatic property in cancer cells carrying PRNP mutations is highly desirable in the future. Interestingly, the age of patients carrying somatic mutations (66 ± 12.8 years) was much older than that of the total cancer patient population (59.1 ± 14.5 years) (Table 2). Since sporadic prion disease has been reported to develop around the ages of 60–70, this was a very interesting finding [38]. In addition, since PrP contributes to several properties of cancer including tumorigenesis, protection of apoptotic stress, and metastasis, further study of the relationship between age and several characteristics of cancers mediated by somatic mutations of the PRNP gene is needed in the future [36,37,39,40]. Furthermore, 83.3% of patients carrying somatic mutations of the PRNP gene showed over 280 mutation counts. This distribution is significantly different from that of the total cancer patient population. In addition, the cancer type of the patients carrying somatic mutations was also significantly different from the total cancer patient population. Notably, although invasive breast carcinoma (9.9%) and glioblastoma (5.4%) account for high percentage of the total cancer patient population, somatic mutation of the PRNP gene has not been identified in these two cancer types. Specifically, because somatic mutations of the PRNP gene in glioblastoma, which occurs in the brain, can be masked by a diagnosis of dementia, the absence of somatic mutations in the PRNP gene in glioblastoma can be explained. Previous study has been reported that transgenic mice carrying a pathogenic mutation of the PRNP gene can lead to spontaneous prion disease [41,42]. In addition, a recent study has been reported that PrPSc were also detected in healthy people, who have not been diagnosed with prion diseases [43]. On the basis of these studies, we postulated that cancer patients carrying pathogenic somatic mutation of the PRNP gene may produce a basal level of PrPSc in peripheral tissues and may not be diagnosed with prion disease. However, to date, there is no clinical evidence for this hypothesis. Since PrP protects cancer cells against apoptotic stress and contributes to tumorigenesis, the difference on distribution of somatic mutation of the PRNP gene may be induced depending on the degree of contribution of PrP to different cancer types [39,40]. Further study to verify functional role of prion protein in various cancer types is needed in the future.
We also analyzed somatic mutations of the PRNP gene in cancer patients by PolyPhen-2, PANTHER, and PROVEAN. Notably, six somatic mutations—P26L, G34R, G119R, G131V, C214G, and Y218C—and five pathogenic mutations—P102L, P105L, G114V, H187R, and E200G—were considered to be damaging to PrP function by all three programs. Since PrPC has also been reported to be related to the survival signaling pathway and copper ion-associated enzyme activity, these somatic mutations may impact the normal function of PrP [44]. In addition, we predicted the amyloid propensity of the somatic mutations in the PRNP gene in cancer patients. Notably, four somatic mutations—L125F, E146Q, R151C, and K204N—were newly identified amyloid-prone somatic mutations in the PRNP gene in cancer patients. In addition, we found several nonsense somatic mutations. These nonsense mutations induced PrP cleavage, which can affect the survival signaling pathway or the aggregation of PrP [6,17,45]. Thus, further investigation of the mutation counts, the absence of somatic mutations in glioblastoma, and these nonsense mutations are highly desirable in the future.
In recent cancer studies, p53 has been demonstrated to play a pivotal role in several types of cancer and showed prion-like aggregation. Aggregation of p53 causes additional deleterious effects in cancer patients [46,47,48]. In addition, although cross-seeding activity between aggregated p53 and PrPSc has not been investigated thus far, the similarity of cross-seeding activities in other misfolded proteins suggests that aggregated p53 may act as a seed to induce the aggregation of PrP [49]. Thus, the detection of PrPSc in cancer patients using Western blot or protein misfolded cyclic amplification (PMCA) is highly desirable in the future.

4. Material and Methods

4.1. Information on the Somatic Mutations in the PRNP Gene in Cancer Patients

The protein sequence of human PrP in Figure 1 was obtained from GenBank at the National Center for Biotechnology Information (NCBI, AAH22532.1). Previously reported pathogenic mutations associated with prion disease were collected from previous studies [6,16,17]. The data on somatic mutations of the PRNP gene in cancer patients were extracted from TCGA database using cBioPortal (http://www.cbioportal.org/) [26]. Among total mutations of the PRNP gene, germline mutations were excluded using the filtering option. Somatic mutations were analyzed using reference sequence from GenBank at the NCBI (NM_000311.5). Clinical data including somatic mutations, age of diagnosis, sex, mutation count, cancer type, and allele frequencies were retrieved from cBioPortal and the data were read by R (https://www.r-project.org/).

4.2. Statistical Analysis

Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). The differences in the distributions of sex, mutation count, and cancer type between the total cancer patient population and the subgroups were compared using the χ2 test. The age of diagnosis was reported as the mean values ± standard deviation (SD). Statistical significance based on p-values was calculated with a one-tailed Student’s t-test for single comparison.

4.3. In Silico Evaluation of Somatic Mutations in the PRNP Gene in Cancer Patients

Somatic mutations in the PRNP gene in cancer patients were evaluated by PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/), PANTHER (http://www.pantherdb.org/), PROVEAN (http://provean.jcvi.org/index.php), and AMYCO (http://bioinf.uab.es/amycov04/) [27,28,29,30]. The effects of sequence variation were evaluated on the basis of protein structure by PolyPhen-2. The PolyPhen-2 score corresponds to the substitution effect and ranges from 0.0 to 1.0. The prediction outcome can be presented as “Benign”, “Possibly damaging”, or “Probably damaging” on the basis of the score. PROVEAN assessed amino acid substitution by building up and comparing the clusters of related sequences and calculating the score. Scores below −2.5 are predicted as “Deleterious” and scores above −2.5 are predicted as “Neutral”. PANTHER analyzes data in groups on the basis of similarities in molecular function and biological processes. PANTHER analyzed preservation time to estimate the substitution of amino acids. The interpretation of preservation time is described as follows: “Probably damaging” is greater than 450; “Possibly damaging” is between 200 and 450; “Probably benign” is less than 200. AMYCO evaluates the impact of variations on the aggregation propensity of prion-like proteins. The AMYCO score corresponds to the substitution effect and ranges from 0.0 to 1.0.

5. Conclusions

In conclusion, we identified 48 somatic mutations in the PRNP gene in 10,967 cancer patients. Among them, eight somatic mutations are pathogenic for prion diseases. We identified significantly different distributions of cancer type, mutation count, and the age of diagnosis between the total cancer patient population and cancer patients carrying PRNP somatic mutations. We found six somatic mutations, these being P26L, G34R, G119R, G131V, C214G, and Y218C, and five pathogenic mutations, these being P102L, P105L, G114V, H187R, and E200G, which can affect PrPC function, along with four aggregation-prone somatic mutations—L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis on the somatic mutations of the PRNP gene in cancer patients.

Author Contributions

Y.-C.K. and B.-H.J. conceived and designed the experiments. Y.-C.K., S.-Y.W., and B.-H.J. analyzed the data. Y.-C.K. and B.-H.J. wrote the paper. All authors read and approved the final manuscript.

Funding

This research was supported by the Basic Science Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2018R1D1A1B07048711). This research was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A1A03015876). This work was supported by the NRF (National Research Foundation of Korea) grant funded by the Korean Government (NRF-2019—Fostering Core Leaders of the Future Basic Science Program/Global Ph.D. Fellowship Program).

Acknowledgments

The results obtained in this study are partially based on data produced by the TCGA Research Network (http://cancergenome.nih.gov/).

Conflicts of Interest

The authors declare no conflict of interest, financial or otherwise.

Abbreviations

PrPScMisfolded prion protein
PrPCNormal prion protein
PrPPrion protein
TCGAThe Cancer Genome Atlas
BSEBovine spongiform encephalopathy
CJDCreutzfeldt–Jakob disease
CWDChronic wasting disease
FFIFatal familial insomnia
GSSGerstmann–Sträussler–Scheinker syndrome
PRNPPrion protein gene

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Cells 09 01480 g001 550
Figure 1. Schematic map of human prion protein (PrP) with somatic mutations of the prion protein gene (PRNP) in cancer patients. Sharps indicate previous reported pathogenic mutations of prion diseases. SP: signal peptide; OPR: octapeptide repeat region.
Figure 1. Schematic map of human prion protein (PrP) with somatic mutations of the prion protein gene (PRNP) in cancer patients. Sharps indicate previous reported pathogenic mutations of prion diseases. SP: signal peptide; OPR: octapeptide repeat region.
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Cells 09 01480 g002 550
Figure 2. Comparison of distributions of patients harboring somatic mutations of the PRNP gene according to six major cancer types. PRNP: distribution of cancer patients harboring somatic mutations of the PRNP gene in six major cancer types. Total: distribution of cancer patients harboring somatic mutations in six major cancer types. *** indicates p < 0.001.
Figure 2. Comparison of distributions of patients harboring somatic mutations of the PRNP gene according to six major cancer types. PRNP: distribution of cancer patients harboring somatic mutations of the PRNP gene in six major cancer types. Total: distribution of cancer patients harboring somatic mutations in six major cancer types. *** indicates p < 0.001.
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Cells 09 01480 g003a 550Cells 09 01480 g003b 550Cells 09 01480 g003c 550
Figure 3. Prediction on amyloid propensity of prion protein (PrP) according to somatic mutations of the prion protein gene (PRNP) gene in cancer patients. $ indicates somatic mutations of the PRNP gene in cancer patients. # indicates previously reported pathogenic mutations of the PRNP gene in prion diseases.
Figure 3. Prediction on amyloid propensity of prion protein (PrP) according to somatic mutations of the prion protein gene (PRNP) gene in cancer patients. $ indicates somatic mutations of the PRNP gene in cancer patients. # indicates previously reported pathogenic mutations of the PRNP gene in prion diseases.
Cells 09 01480 g003aCells 09 01480 g003bCells 09 01480 g003c
Table
Table 1. Classification of pathogenic mutations of prion disease according to clinical phenotypes in previous studies.
Table 1. Classification of pathogenic mutations of prion disease according to clinical phenotypes in previous studies.
Clinical PhenotypesMutations
Creutzfeldt–Jakob Disease (CJD)G114V, D178N-129V, V180I, T183A, T188K, E196K, E196A, E200K, E200G, V203I, R208H, V210I, E211Q, I215V, M232R, P238S, double octapeptide deletion, and octapeptide insertions
Fatal familial insomnia (FFI)D178N-129M
Gerstmann–Sträussler–Scheinker syndrome (GSS)P102L, P105L, P105T, P105S, A117V, G131V, Y145*, Q160*, V176G, H187R, F198S, D202N, Q212P, Q217R, Y226*, Q227*, and M232T
OthersS17G, P39L, Y163*, D167N, D187fs, and R208C
Others: includes unique phenotypes of dementia. *: stop codon. fs: frame shift.
Table
Table 2. Detailed information on the 48 somatic mutations in cancer patients.
Table 2. Detailed information on the 48 somatic mutations in cancer patients.
Sample IDSexAgeCancer TypeAJCCMSC AJCCTSC MutationMutation TypeAllele Frequency# Mut
TCGA-4Z-AA7Q-01M79Bladder urothelial carcinomaM0 T3AE146QMissense0.19222
TCGA-5N-A9KM-01F73Bladder urothelial carcinomaMX T4AM1?Nonstart0.36189
TCGA-IR-A3LK-01F69Cervical squamous cell carcinomaM0T1B2G131VMissense0.141189
TCGA-KN-8428-01M71Chromophobe renal cell carcinomaNAT2V203IMissense0.20673
TCGA-CK-5916-01F71Colon adenocarcinomaM0T1V180IMissense0.251407
TCGA-EE-A29V-06M85Cutaneous melanomaM0T3BG92EMissense0.421012
TCGA-EB-A41A-01M90Cutaneous melanomaM0T4BL125FMissense0.441533
TCGA-D3-A2JC-06F53Cutaneous melanomaM0T0M166IMissense0.113148
TCGA-D3-A8GM-06M73Cutaneous melanomaM0T3BG86SMissense0.093288
TCGA-YD-A9TA-06M75Cutaneous melanomaNANAH61YMissense0.292782
TCGA-L5-A43J-01M90Esophageal squamous cell carcinomaMXT3R25CMissense0.20700
TCGA-F7-A624-01M73Head and neck squamous cell carcinomaM0T2R208HMissense0.162744
TCGA-VQ-A91D-01M70Intestinal type stomach adenocarcinomaM0T4BR208CMissense0.252140
TCGA-67-3771-01F77Lung adenocarcinomaM0T1N173HMissense0.12951
TCGA-44-5644-01F51Lung adenocarcinomaNAT2AG5AMissense0.34908
TCGA-69-A59K-01F60Lung adenocarcinomaM0T3G119RMissense0.21438
TCGA-17-Z023-01NANALung adenocarcinomaNANAY49CMissense0.23362
TCGA-17-Z026-01NANALung adenocarcinomaNANAE211QMissense0.19873
TCGA-22-5489-01M64Lung squamous cell carcinomaM0T1BY145CMissense0.21227
TCGA-63-A5MM-01F69Lung squamous cell carcinomaM0T2H177NMissense0.231070
TCGA-NC-A5HH-01M53Lung squamous cell carcinomaM0T1W16SMissense0.27314
TCGA-G7-6790-01M57Papillary renal cell carcinomaMXT1AQ217KMissense0.0971
TCGA-F9-A97G-01M79Papillary renal cell carcinomaM0T3V252LMissense0.2062
TCGA-AG-A002-01M35Rectal adenocarcinomaM0T2P26LMissense0.4511,438
TCGA-B0-5713-01F75Renal clear cell carcinomaM0T3BE221GMissense0.3097
TCGA-25-1313-01F62Serous ovarian cancerNANAG131RMissense0.37179
TCGA-VQ-A8PO-01M74Signet ring cell carcinoma of the stomachM0T4AM129TMissense0.23751
TCGA-BR-6452-01F78Stomach adenocarcinomaM0T3I244FMissense0.195050
TCGA-CG-5717-01M58Stomach adenocarcinomaM0T2BR151CMissense0.34117
TCGA-CG-5723-01M83Stomach adenocarcinomaM0T2V209MMissense0.081606
TCGA-VQ-A8PP-01M76Tubular stomach adenocarcinomaM0T4K104EMissense0.361328
TCGA-DX-AB2Z-01F87Undifferentiated pleomorphic sarcomaNANAR148HMissense0.1169
TCGA-N7-A4Y0-01F65Uterine carcinosarcomaNANAC214GMissense0.64709
TCGA-ND-A4WC-01NANAUterine carcinosarcomaNANAH85NMissense0.203669
TCGA-B5-A0JY-01F50Uterine endometrioid carcinomaNANAK204NMissense0.349713
TCGA-D1-A17Q-01F54Uterine endometrioid carcinomaNANAD167NMissense0.405945
TCGA-AP-A1DV-01F59Uterine endometrioid carcinomaNANAR25CMissense0.5212,071
TCGA-FI-A2D5-01F56Uterine endometrioid carcinomaNANAD202NMissense0.3813,874
TCGA-AJ-A3EL-01F47Uterine endometrioid carcinomaNANAL11IMissense0.407391
TCGA-AP-A0LT-01F57Uterine endometrioid carcinomaNANAE196Rfs*10Frame shift del0.28638
TCGA-AP-A1DV-01F59Uterine endometrioid carcinomaNANAY218CMissense0.4212,071
TCGA-AX-A3FT-01F64Uterine endometrioid carcinomaNANAQ75Sfs*35Frame shift del0.231281
TCGA-B5-A1MX-01F47Uterine endometrioid carcinomaNANAG92*Nonsense0.335699
TCGA-BG-A222-01F49Uterine endometrioid carcinomaNANAG34RMissense0.454276
TCGA-DF-A2KU-01FNAUterine endometrioid carcinomaNANAS230LMissense0.3010,058
TCGA-EO-A22R-F56Uterine endometrioid carcinomaNANAS230LMissense0.3012,783
TCGA-EY-A1GK-01F74Uterine endometrioid carcinomaNANAG35Afs*75Frame shift del0.30841
TCGA-A5-A0G2-01F57Uterine serous carcinomaNANAD18NMissense0.1825,730
AJCCMSC: American Joint Committee on Cancer Metastasis Stage Code. AJCCTSC: American Joint Committee on Cancer Tumor Stage Code. # Mut: Total number of non-synonymous mutation in the sample. M0: No evidence of distant metastasis. MX: Distant metastasis cannot be assessed. NA: Not available. Shaded boxes indicate pathogenic somatic mutations of prion diseases. *: stop codon.
Table
Table 3. Summary of information on the cancer patients carrying somatic mutations in the PRNP gene.
Table 3. Summary of information on the cancer patients carrying somatic mutations in the PRNP gene.
Characteristics All Cancer PatientsSubgroup 1Subgroup 2
Number of patients 10,953478
% compared to all cancer patients-0.43%0.07%
% compared to subgroup 1--17.02%
Number of samples 10,967488
% compared to all cancer patients 0.44%0.07%
% compared to subgroup 1--16.67%
Diagnosis age (mean ± SD) 59.1 ± 14.566 ± 12.866.3 ± 7.8
p-value compared to all cancer patients 0.0007420.093018
p-value compared to subgroup 1--0.477389
Sex, N (%)Male4866 (44.4%)18 (37.5%)3 (37.5%)
Female5315 (48.5%)27 (56.2%)4 (50.0%)
NA772 (7.0%)3 (6.3%)1 (12.5%)
Total10,95348 8
p-value compared to all cancer patients-0.300.79
p-value compared to subgroup 1--0.89
Mutation count<1006798 (67.3%)4 (8.3%)0 (0%)
100 ≤ x < 2001516 (15.0%)2 (4.2%)0 (0%)
200 ≤ x < 280455 (4.5%)2 (4.2%)0 (0%)
>2801328 (13.2%)40 (83.3%)8 (100%)
Total 10,097 (100%)488
p-value compared to all cancer patients-<0.000012.3 × 10−11
p-value compared to subgroup 1--0.67
Cancer type, N (%)Invasive breast carcinoma1084 (9.9%)0 (0%)0 (0%)
Non-small cell lung cancer1053 (9.6%)8 (16.7%)1 (12.5%)
Colorectal adenocarcinoma594 (5.4%)2 (4.2%)1 (12.5%)
Glioblastoma592 (5.4%)0 (0%)0 (0%)
Endometrial carcinoma586 (5.3%)16 (33.3%)2 (25.0%)
Ovarian epithelial tumor585 (5.3%)1 (2.1%)0
Head and neck squamous cell carcinoma523 (4.8%)1 (2.1%)1 (12.5%)
Esophagogastric adenocarcinoma514 (4.7%)5 (10.4%)1 (12.5%)
Diffuse glioma513 (4.7%)0 (0%)0 (0%)
Renal clear cell carcinoma512 (4.7%)1 (2.1%)0 (0%)
Well-differentiated thyroid500 (4.6%)0 (0%)0 (0%)
Prostate adenocarcinoma494 (4.5%)0 (0%)0 (0%)
Melanoma448 (4.1%)5 (10.4%)0 (0%)
Bladder urothelial carcinoma411 (3.7%)2 (4.2%)0 (0%)
Hepatocellular carcinoma369 (3.4%)0 (0%)0 (0%)
Renal non-clear cell carcinoma348 (3.2%)3 (6.3%)1 (12.5%)
Sarcoma255 (2.3%)1 (2.1%)0 (0%)
Cervical squamous cell carcinoma251 (2.3%)1 (2.1%)1 (12.5%)
Leukemia200 (1.8%)0 (0%)0 (0%)
Pancreatic adenocarcinoma184 (1.7%)0 (0%)0 (0%)
Pheochromocytoma147 (1.3%)0 (0%)0 (0%)
Thymic epithelial tumor123 (1.1%)0 (0%)0 (0%)
Esophageal squamous cell carcinoma95 (0.9%)1 (2.1%)0 (0%)
Adrenocortical carcinoma92 (0.8%)0 (0%)0 (0%)
Pleural mesothelioma87 (0.8%)0 (0%)0 (0%)
Non-seminomatous germ cell tumor86 (0.8%)0 (0%)0 (0%)
Ocular melanoma80 (0.7%)0 (0%)0 (0%)
Seminoma63 (0.6%)0 (0%)0 (0%)
Mature B-cell neoplasms48 (0.4%)0 (0%)0 (0%)
Cervical adenocarcinoma46 (0.4%)0 (0%)0 (0%)
Cholangiocarcinoma36 (0.3%)0 (0%)0 (0%)
Miscellaneous neuroepithelial tumor31 (0.3%)0 (0%)0 (0%)
Undifferentiated stomach adenocarcinoma13 (0.1%)1 (2.1%)0 (0%)
Fibrolamellar carcinoma3 (<0.1%)0 (0%)0 (0%)
Encapsulated glioma1 (<0.1%)0 (0%)0 (0%)
Total 10,967488
p-value compared to all cancer patients-6 × 10−120.96
p-value compared to subgroup 1--NA
Subgroup 1: carriers of PRNP somatic mutations. Subgroup 2: carriers of PRNP pathogenic somatic mutations of prion disease. NA: not available. Shaded boxes indicate pathogenic somatic mutations of prion disease. Bold text indicates statistical significance (p < 0.05).
Table
Table 4. In silico annotations of PRNP somatic mutations in cancer patients.
Table 4. In silico annotations of PRNP somatic mutations in cancer patients.
MutationsPolyPhen-2PANTHERPROVEAN
ScorePredictionPreservation TimePredictionScorePrediction
$ G5A0.729Possibly damaging176Probably benign−1.238Neutral
$ L11I0.161Benign176Probably benign−0.306Neutral
$ W16S0.546Possibly damaging176Probably benign−1.237Neutral
# S17G0.528Possibly damaging176Probably benign−0.239Neutral
$ D18N1.000Probably damaging176Probably benign−0.104Neutral
$ R25C1.000Probably damaging176Probably benign−1.801Neutral
$ P26L0.995Probably damaging324Possibly damaging−3.263Deleterious
$ G34R1.000Probably damaging220Possibly damaging−3.889Deleterious
# P39L1.000Probably damaging361Possibly damaging−4.000Deleterious
$ Y49C1.000Probably damaging176Probably benign−2.222Neutral
$ H61Y0.975Probably damaging176Probably benign−1.021Neutral
$ H85N0.975Probably damaging176Probably benign−0.833Neutral
$ G86S1.000Probably damaging324Possibly damaging−0.995Neutral
$ G92E1.000Probably damaging176Probably benign−1.253Neutral
# P102L1.000Probably damaging361Possibly damaging−3.392Deleterious
# P105L1.000Probably damaging324Possibly damaging−3.271Deleterious
# P105T0.998Probably damaging324Possibly damaging−2.333Neutral
# P105S0.997Probably damaging324Possibly damaging−1.496Neutral
$ K104E0.974Probably damaging324Possibly damaging−1.208Neutral
# G114V1.000Probably damaging220Possibly damaging−2.540Deleterious
# A117V0.999Probably damaging176Probably benign−1.263Neutral
$ G119R1.000Probably damaging361Possibly damaging−2.586Deleterious
$ L125F1.000Probably damaging324Possibly damaging−0.398Neutral
$ M129T0.181Benign324Possibly damaging−1.156Neutral
$ G131R1.000Probably damaging361Possibly damaging−2.451Neutral
#,$ G131V1.000Probably damaging361Possibly damaging−2.879Deleterious
$ Y145C0.997Probably damaging220Possibly damaging−1.742Neutral
$ E146Q0.992Probably damaging361Possibly damaging−0.985Neutral
$ R148H1.000Probably damaging361Possibly damaging−1.735Neutral
$ R151C0.009Benign220Possibly damaging−2.016Neutral
$ M166I0.000Benign30Probably benign0.254Neutral
#,$ D167N0.001Benign220Possibly damaging−0.631Neutral
$ N173H0.952Probably damaging176Probably benign−1.573Neutral
# V176G0.998Probably damaging361Possibly damaging−2.253Neutral
$ H177N0.313Benign220Possibly damaging−0.455Neutral
# D178N-129M1.000Probably damaging361Possibly damaging−1.531Neutral
# D178N-129V1.000Probably damaging361Possibly damaging−1.451Neutral
#,$ V180I0.009Benign220Possibly damaging−0.11Neutral
# T183A0.978Probably damaging324Possibly damaging−1.785Neutral
# H187R0.989Probably damaging220Possibly damaging−2.607Deleterious
# T188K0.996Probably damaging324Possibly damaging−0.550Neutral
# E196K0.624Possibly damaging220Possibly damaging−0.641Neutral
# E196A0.472Possibly damaging220Possibly damaging−1.206Neutral
# F198S0.994Probably damaging220Possibly damaging−0.792Neutral
# E200K0.995Probably damaging361Possibly damaging−1.478Neutral
# E200G0.994Probably damaging361Possibly damaging−3.245Deleterious
#,$ D202N1.000Probably damaging220Possibly damaging−1.118Neutral
#,$ V203I0.001Benign176Probably benign−0.004Neutral
$ K204N0.898Possibly damaging220Possibly damaging−1.815Neutral
#,$ R208C1.000Probably damaging220Possibly damaging−2.324Neutral
#,$ R208H0.999Probably damaging220Possibly damaging−0.855Neutral
$ V209M0.613Possibly damaging324Possibly damaging−1.03Neutral
# V210I0.803Possibly damaging220Possibly damaging0.039Neutral
#,$ E211Q0.992Probably damaging220Possibly damaging−0.36Neutral
# Q212P0.930Possibly damaging220Possibly damaging−1.665Neutral
$ C214G0.975Probably damaging361Possibly damaging−4.402Deleterious
# I215V0.000Benign220Possibly damaging−0.099Neutral
# Q217R0.961Probably damaging220Possibly damaging−1.306Neutral
$ Q217K0.942Probably damaging220Possibly damaging−1.186Neutral
$ Y218C1.000Probably damaging361Possibly damaging−3.626Deleterious
$ E221G0.651Possibly damaging220Possibly damaging−1.244Neutral
$ S230L0.947Possibly damaging97Probably benign−1.372Neutral
# M232R0.082Benign91Probably benign−1.167Neutral
# M232T0.000Benign91Probably benign−0.825Neutral
# P238S1.000Probably damaging361Possibly damaging−1.189Neutral
$ I244F0.001Benign176Probably benign−0.939Neutral
$ V252L0.990Probably damaging176Probably benign−0.411Neutral
$ indicates somatic mutations of the PRNP gene in cancer patients. # indicates previously reported pathogenic mutations of the PRNP gene in prion diseases. Shaded boxes indicate the mutations that were predicted to be deleterious by all three programs.

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Kim, Y.-C.; Won, S.-Y.; Jeong, B.-H. Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients. Cells 2020, 9, 1480. https://doi.org/10.3390/cells9061480

AMA Style

Kim Y-C, Won S-Y, Jeong B-H. Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients. Cells. 2020; 9(6):1480. https://doi.org/10.3390/cells9061480

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Kim, Yong-Chan, Sae-Young Won, and Byung-Hoon Jeong. 2020. "Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients" Cells 9, no. 6: 1480. https://doi.org/10.3390/cells9061480

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