Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation
Abstract To get a better understanding of the genetic basis of primary signet ring cell carcinoma (SRCC) of the bladder, which is highly rare and not yet explored. First, by using immunohistochemistry to find histological pathological characteristics. Second, a massively parallel whole‐exome sequenc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.5121 |
| _version_ | 1797893221376851968 |
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| author | Mohammed Alradhi Shuang Wen Mohammed Safi Abdullah Al‐danakh Honglong Wang Abdullah Shopit Min Sun Bo Fan Xiancheng Li |
| author_facet | Mohammed Alradhi Shuang Wen Mohammed Safi Abdullah Al‐danakh Honglong Wang Abdullah Shopit Min Sun Bo Fan Xiancheng Li |
| author_sort | Mohammed Alradhi |
| collection | DOAJ |
| description | Abstract To get a better understanding of the genetic basis of primary signet ring cell carcinoma (SRCC) of the bladder, which is highly rare and not yet explored. First, by using immunohistochemistry to find histological pathological characteristics. Second, a massively parallel whole‐exome sequencing (WES) was performed on a 58‐year‐old male patient who had painless macroscopic hematuria and was pathologically diagnosed with primary SRCC of the bladder, followed by comparing with genes of ordinary urothelial cancer (UC) from TCGA. Furthermore, a population‐based analysis using the SEER database was performed to investigate the prognosis (SRCC vs. UC). We identified 63 copy number variations (CNVs) with gain counts and 181 CNVs with loss counts. Totally 4515 mutations were discovered in C > T with a success rate of greater than 89%. The most frequently mutated pathway was RTK‐RAS which has 85 genes involved in carcinogenic signaling. Final screening on predisposing genes is performed after filtering based on ACMG. Moreover, several driver genes, including NBN, KCTD18, SPATA13, ANKRD36, OR2L5, MALRD1, and LSMEM1, were detected. Sanger sequencing of germline DNA revealed the presence of a mutant base A/G of OR2L5 in the sequence, which was discovered for the first time in primary SRCC of the bladder. Furthermore, the immunohistochemical profile showed that primary SRCC of the bladder were positive for CK7, CK20, GATA‐3, and expression of CK(AE1/AE2), EMA, and Ki67. In the SEER‐based study, the patients with primary SRCC of the bladder got a worse prognosis compared to those with UC with median months overall survival (OS) 14 vs. 41, respectively, P = 0001, even after adjusting the variables in the Cox regression model, the SRCC of the bladder showed worse survival HR = 1.119, 95% CI = (1.081–1.328), P = 0.0001. These results imply that suppression of potential driver mutations may be a viable adjuvant treatment approach for primary SRCC in the bladder in place of standard chemotherapy, a possibility that warrants further clinical investigation. |
| first_indexed | 2024-04-10T06:49:24Z |
| format | Article |
| id | doaj.art-5c440203cdfb48e2bd7f7e5fd1d73446 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-10T06:49:24Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
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| series | Cancer Medicine |
| spelling | doaj.art-5c440203cdfb48e2bd7f7e5fd1d734462023-02-28T08:51:56ZengWileyCancer Medicine2045-76342023-02-011243931395110.1002/cam4.5121Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutationMohammed Alradhi0Shuang Wen1Mohammed Safi2Abdullah Al‐danakh3Honglong Wang4Abdullah Shopit5Min Sun6Bo Fan7Xiancheng Li8Department of Urology, Second Affiliated Hospital of Dalian Medical University Dalian ChinaDepartment of Pathology, Dalian Friendship Hospital Dalian ChinaDepartment of Respiratory Diseases Shandong Second Provincial General Hospital Shandong University Shandong ChinaDepartment of Urology, First Affiliated Hospital of Dalian Medical University Dalian ChinaDepartment of Pathology, Dalian Friendship Hospital Dalian ChinaDepartment of Pharmacology, Dalian Medical University Dalian ChinaDepartment of General Surgery, Taihe Hospital, Hubei University of Medicine Hubei ChinaDepartment of Urology, Second Affiliated Hospital of Dalian Medical University Dalian ChinaDepartment of Urology, Second Affiliated Hospital of Dalian Medical University Dalian ChinaAbstract To get a better understanding of the genetic basis of primary signet ring cell carcinoma (SRCC) of the bladder, which is highly rare and not yet explored. First, by using immunohistochemistry to find histological pathological characteristics. Second, a massively parallel whole‐exome sequencing (WES) was performed on a 58‐year‐old male patient who had painless macroscopic hematuria and was pathologically diagnosed with primary SRCC of the bladder, followed by comparing with genes of ordinary urothelial cancer (UC) from TCGA. Furthermore, a population‐based analysis using the SEER database was performed to investigate the prognosis (SRCC vs. UC). We identified 63 copy number variations (CNVs) with gain counts and 181 CNVs with loss counts. Totally 4515 mutations were discovered in C > T with a success rate of greater than 89%. The most frequently mutated pathway was RTK‐RAS which has 85 genes involved in carcinogenic signaling. Final screening on predisposing genes is performed after filtering based on ACMG. Moreover, several driver genes, including NBN, KCTD18, SPATA13, ANKRD36, OR2L5, MALRD1, and LSMEM1, were detected. Sanger sequencing of germline DNA revealed the presence of a mutant base A/G of OR2L5 in the sequence, which was discovered for the first time in primary SRCC of the bladder. Furthermore, the immunohistochemical profile showed that primary SRCC of the bladder were positive for CK7, CK20, GATA‐3, and expression of CK(AE1/AE2), EMA, and Ki67. In the SEER‐based study, the patients with primary SRCC of the bladder got a worse prognosis compared to those with UC with median months overall survival (OS) 14 vs. 41, respectively, P = 0001, even after adjusting the variables in the Cox regression model, the SRCC of the bladder showed worse survival HR = 1.119, 95% CI = (1.081–1.328), P = 0.0001. These results imply that suppression of potential driver mutations may be a viable adjuvant treatment approach for primary SRCC in the bladder in place of standard chemotherapy, a possibility that warrants further clinical investigation.https://doi.org/10.1002/cam4.5121immunohistochemistryOR2L5primary signet ring cell carcinomaurinary bladderwhole‐exome sequencing |
| spellingShingle | Mohammed Alradhi Shuang Wen Mohammed Safi Abdullah Al‐danakh Honglong Wang Abdullah Shopit Min Sun Bo Fan Xiancheng Li Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation Cancer Medicine immunohistochemistry OR2L5 primary signet ring cell carcinoma urinary bladder whole‐exome sequencing |
| title | Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation |
| title_full | Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation |
| title_fullStr | Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation |
| title_full_unstemmed | Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation |
| title_short | Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation |
| title_sort | molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel or2l5 mutation |
| topic | immunohistochemistry OR2L5 primary signet ring cell carcinoma urinary bladder whole‐exome sequencing |
| url | https://doi.org/10.1002/cam4.5121 |
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