Genomic analysis and biomarker discovery of thymic cancer based on whole exome sequencing: A retrospective cohort study_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

XIANG Run ¹ , XIE Shaohua ¹ , LIAO Qiong ² , LI Qiang ¹ , SHAO Weikang ³ ,  LI Juan ⁴

1. Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, P. R. China;
2. Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, P. R. China;
3. Genecast Biotechnology Co., Ltd., Wuxi, 214000, Jiangsu, P. R. China;
4. Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, P. R. China;

Corresponding author：

LI Juan, Email: dr.lijuan@hotmail.com

Keywords：

Thymic carcinoma; gene mutation; whole-exome sequencing; retrospective cohort study

DOI：

10.7507/1007-4848.202310011

Video：

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Objective To examined gene mutations in thymic carcinoma (TC) patients and to explore prognostic correlates and potential targets for therapy. Methods We retrospectively included TC patients in Sichuan Cancer Hospital between January 2015 and Febuary 2021.Whole-exome sequencing was performed on tumor tissues from TC patients and their control peripheral blood samples, and the raw data were subjected to bioinformatics analysis and statistical analysis. Results We finally included 24 TC patients with 16 males and 8 females at a median age of 55 (42-74) years. The highest frequency of single nucleotide mutations in this cohort were in the TTN gene (42%), HSPG2 (29%), and OBSCN (29%). Higher frequency of copy number variations occurred in ZNF276 gene (54%, loss), BEND3 (50%, loss), DHODH (50%, loss), and VAC14 (50%, loss). Microsatellite instability (MSI) phenotype was found in 25% of the patients, and the mean tumor mutation burden (TMB) was 9.86. Conclusion This study is the first comprehensive analysis of the mutation profile of thymic carcinoma in China to date. The mutation frequencies of TTN, OBSCN, and ZNF276 genes were high. The biomarker analysis suggests that patients may benefit from immunotherapy and have a long effective survival.

Citation： XIANG Run, XIE Shaohua, LIAO Qiong, LI Qiang, SHAO Weikang, LI Juan. Genomic analysis and biomarker discovery of thymic cancer based on whole exome sequencing: A retrospective cohort study. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2024, 31(2): 288-303. doi: 10.7507/1007-4848.202310011 Copy

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2.	Kondo K, Monden Y. Therapy for thymic epithelial tumors: A clinical study of 1 320 patients from Japan. Ann Thorac Surg, 2003, 76(3): 878-884.
3.	Eng TY, Fuller CD, Jagirdar J, et al. Thymic carcinoma: State of the art review. Int J Radiat Oncol Biol Phys, 2004, 59(3): 654-664.
4.	Ettinger DS, Riely GJ, Akerley W, et al. Thymomas and thymic carcinomas: Clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2013, 11(5): 562-576.
5.	Marx A, Rieker R, Toker A, et al. Thymic carcinoma: Is it a separate entity? From molecular to clinical evidence. Thorac Surg Clin, 2011, 21(1): 25-31.
6.	Policies and reporting guidelines for small biopsy specimens of mediastinal masses. J Thorac Oncol, 2011, 6(7 Suppl 3): S1724-9.
7.	Ströbel P, Hohenberger P, Marx A. Thymoma and thymic carcinoma: molecular pathology and targeted therapy. J Thorac Oncol, 2010, 5(10 Suppl 4): S286-290.
8.	Moran CA, Suster S. Thymic carcinoma: Current concepts and histologic features. Hematol Oncol Clin North Am, 2008, 22(3): 393-407.
9.	Jovanovic D, Markovic J, Ceriman V, et al. Correlation of genomic alterations and PD-L1 expression in thymoma. J Thorac Dis, 2020, 12(12): 7561-7570.
10.	He Y, Ramesh A, Gusev Y, et al. Molecular predictors of response to pembrolizumab in thymic carcinoma. Cell Rep Med, 2021, 2(9): 100392.
11.	Shimada M, Taniguchi H, Yamaguchi H, et al. Genetic profile of thymic epithelial tumors in the Japanese population: An exploratory study examining potential therapeutic targets. Transl Lung Cancer Res, 2023, 12(4): 707-718.
12.	Szpechcinski A, Szolkowska M, Winiarski S, et al. Targeted next-generation sequencing of thymic epithelial tumours revealed pathogenic variants in KIT, ERBB2, KRAS, and TP53 in 30% of thymic carcinomas. Cancers (Basel), 2022, 14(14): 3388.
13.	Tsukaguchi A, Ihara S, Yasuoka H, et al. Lenvatinib-refractory thymic mucinous carcinoma with PIK3CA mutation; proceedings of the International Cancer Conference Journal, 2023. Springer.
14.	Chen S, Zhou Y, Chen Y, et al. Fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics, 2018, 34(17): i884-i890.
15.	Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 2009, 25(14): 1754-1760.
16.	Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. Bioinformatics, 2009, 25(16): 2078-2079.
17.	Karczewski KJ, Weisburd B, Thomas B, et al. The ExAC browser: Displaying reference data information from over 60 000 exomes. Nucleic Acids Res, 2017, 45(D1): D840-D845.
18.	Gudmundsson S, Singer-Berk M, Watts NA, et al. Variant interpretation using population databases: Lessons from gnomAD. Hum Mutat, 2022, 43(8): 1012-1030.
19.	Mayakonda A, Lin DC, Assenov Y, et al. Maftools: Efficient and comprehensive analysis of somatic variants in cancer. Genome Res, 2018, 28(11): 1747-1756.
20.	Analysis of 100, 000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med, 2017, 9(1): 1-14.
21.	Niu B, Ye K, Zhang Q, et al. MSIsensor: Microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics, 2014, 30(7): 1015-1016.
22.	Mroz EA, Tward AD, Hammon RJ, et al. Intra-tumor genetic heterogeneity and mortality in head and neck cancer: Analysis of data from the Cancer Genome Atlas. PLoS Med, 2015, 12(2): e1001786.
23.	Szolek A, Schubert B, Mohr C, et al. OptiType: Precision HLA typing from next-generation sequencing data. Bioinformatics, 2014, 30(23): 3310-3316.
24.	Feng K, Liu Y, Zhao Y, et al. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: Results from a phaseⅡstudy. J Immunother Cancer, 2020, 8(1): e000367.
25.	Favero F, Joshi T, Marquard AM, et al. Sequenza: Allele-specific copy number and mutation profiles from tumor sequencing data. Ann Oncol, 2015, 26(1): 64-70.
26.	Yu G, Wang LG, Han Y, et al. ClusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
27.	Xu S, Li X, Zhang H, et al. Frequent genetic alterations and their clinical significance in patients with thymic epithelial tumors. Front Oncol, 2021, 11: 667148.
28.	Roden AC. Molecular changes are infrequent in thymic carcinomas but might represent targetable mutations. Mediastinum, 2017, 1: 23.
29.	Hackman P, Vihola A, Haravuori H, et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet, 2002, 71(3): 492-500.
30.	Han X, Chen J, Wang J, et al. TTN mutations predict a poor prognosis in patients with thyroid cancer. Biosci Rep, 2022, 42(7): BSR20221168.
31.	Zheng QX, Wang J, Gu XY, et al. TTN-AS1 as a potential diagnostic and prognostic biomarker for multiple cancers. Biomed Pharmacother, 2021, 135: 111169.
32.	Fang X, Zhong C, Weng S, et al. Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: Study protocol of a randomized, open-label, multicentric study. BMC Cancer, 2023, 23(1): 676.
33.	Liu Z, Wang L, Guo C, et al. TTN/OBSCN 'Double-Hit' predicts favourable prognosis, 'immune-hot' subtype and potentially better immunotherapeutic efficacy in colorectal cancer. J Cell Mol Med, 2021, 25(7): 3239-3251.
34.	Radovich M, Pickering CR, Felau I, et al. The integrated genomic landscape of thymic epithelial tumors. Cancer Cell, 2018, 33(2): 244-258.
35.	Du H, Xie S, Guo W, et al. The prognostic value of tumor mutation burden and immune cell infiltration in thymic epithelial tumors. Ann Clin Lab Sci, 2021, 51(1): 44-54.
36.	Prays J, Ortiz-Villalón C. Molecular landscape of thymic epithelial tumors. Semin Diagn Pathol, 2022, 39(2): 131-136.
37.	Yang W, Chen S, Cheng X, et al. Characteristics of genomic mutations and signaling pathway alterations in thymic epithelial tumors. Ann Transl Med, 2021, 9(22): 1659.
38.	Wang F, Wei XL, Wang FH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ⅰb/Ⅱ clinical trial NCT02915432. Ann Oncol, 2019, 30(9): 1479-1486.
39.	Klempner SJ, Fabrizio D, Bane S, et al. Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: A review of current evidence. Oncologist, 2020, 25(1): e147-e159.
40.	Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.
41.	Trabucco SE, Gowen K, Maund SL, et al. A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability-high cases in 67, 000 patient samples. J Mol Diagn, 2019, 21(6): 1053-1066.
42.	Repetto M, Conforti F, Pirola S, et al. Thymic carcinoma with lynch syndrome or microsatellite instability, a rare entity responsive to immunotherapy. Eur J Cancer, 2021, 153: 162-167.
43.	Mroz EA, Rocco JW. Intra-tumor heterogeneity in head and neck cancer and its clinical implications. World J Otorhinolaryngol Head Neck Surg, 2016, 2(2): 60-67.
44.	McDonald KA, Kawaguchi T, Qi Q, et al. Tumor heterogeneity correlates with less immune response and worse survival in breast cancer patients. Ann Surg Oncol, 2019, 26(7): 2191-2199.
45.	Nguyen L, WM Martens J, Van Hoeck A, et al. Pan-cancer landscape of homologous recombination deficiency. Nat Commun, 2020, 11(1): 5584.
46.	Kim H, Ahn S, Kim H, et al. The prevalence of homologous recombination deficiency (HRD) in various solid tumors and the role of HRD as a single biomarker to immune checkpoint inhibitors. J Cancer Res Clin Oncol, 2022, 148(9): 2427-2435.
47.	Rempel E, Kluck K, Beck S, et al. Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD). NPJ Precis Oncol, 2022, 6(1): 36.

1. Listed NA. Proceedings of the First International Conference on Thymic Malignancies. August 20-21, 2009. Bethesda, Maryland, USA. J Thorac Oncol, 2010, 5(4): 259-370.
2. Kondo K, Monden Y. Therapy for thymic epithelial tumors: A clinical study of 1 320 patients from Japan. Ann Thorac Surg, 2003, 76(3): 878-884.
3. Eng TY, Fuller CD, Jagirdar J, et al. Thymic carcinoma: State of the art review. Int J Radiat Oncol Biol Phys, 2004, 59(3): 654-664.
4. Ettinger DS, Riely GJ, Akerley W, et al. Thymomas and thymic carcinomas: Clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2013, 11(5): 562-576.
5. Marx A, Rieker R, Toker A, et al. Thymic carcinoma: Is it a separate entity? From molecular to clinical evidence. Thorac Surg Clin, 2011, 21(1): 25-31.
6. Policies and reporting guidelines for small biopsy specimens of mediastinal masses. J Thorac Oncol, 2011, 6(7 Suppl 3): S1724-9.
7. Ströbel P, Hohenberger P, Marx A. Thymoma and thymic carcinoma: molecular pathology and targeted therapy. J Thorac Oncol, 2010, 5(10 Suppl 4): S286-290.
8. Moran CA, Suster S. Thymic carcinoma: Current concepts and histologic features. Hematol Oncol Clin North Am, 2008, 22(3): 393-407.
9. Jovanovic D, Markovic J, Ceriman V, et al. Correlation of genomic alterations and PD-L1 expression in thymoma. J Thorac Dis, 2020, 12(12): 7561-7570.
10. He Y, Ramesh A, Gusev Y, et al. Molecular predictors of response to pembrolizumab in thymic carcinoma. Cell Rep Med, 2021, 2(9): 100392.
11. Shimada M, Taniguchi H, Yamaguchi H, et al. Genetic profile of thymic epithelial tumors in the Japanese population: An exploratory study examining potential therapeutic targets. Transl Lung Cancer Res, 2023, 12(4): 707-718.
12. Szpechcinski A, Szolkowska M, Winiarski S, et al. Targeted next-generation sequencing of thymic epithelial tumours revealed pathogenic variants in KIT, ERBB2, KRAS, and TP53 in 30% of thymic carcinomas. Cancers (Basel), 2022, 14(14): 3388.
13. Tsukaguchi A, Ihara S, Yasuoka H, et al. Lenvatinib-refractory thymic mucinous carcinoma with PIK3CA mutation; proceedings of the International Cancer Conference Journal, 2023. Springer.
14. Chen S, Zhou Y, Chen Y, et al. Fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics, 2018, 34(17): i884-i890.
15. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 2009, 25(14): 1754-1760.
16. Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. Bioinformatics, 2009, 25(16): 2078-2079.
17. Karczewski KJ, Weisburd B, Thomas B, et al. The ExAC browser: Displaying reference data information from over 60 000 exomes. Nucleic Acids Res, 2017, 45(D1): D840-D845.
18. Gudmundsson S, Singer-Berk M, Watts NA, et al. Variant interpretation using population databases: Lessons from gnomAD. Hum Mutat, 2022, 43(8): 1012-1030.
19. Mayakonda A, Lin DC, Assenov Y, et al. Maftools: Efficient and comprehensive analysis of somatic variants in cancer. Genome Res, 2018, 28(11): 1747-1756.
20. Analysis of 100, 000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med, 2017, 9(1): 1-14.
21. Niu B, Ye K, Zhang Q, et al. MSIsensor: Microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics, 2014, 30(7): 1015-1016.
22. Mroz EA, Tward AD, Hammon RJ, et al. Intra-tumor genetic heterogeneity and mortality in head and neck cancer: Analysis of data from the Cancer Genome Atlas. PLoS Med, 2015, 12(2): e1001786.
23. Szolek A, Schubert B, Mohr C, et al. OptiType: Precision HLA typing from next-generation sequencing data. Bioinformatics, 2014, 30(23): 3310-3316.
24. Feng K, Liu Y, Zhao Y, et al. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: Results from a phaseⅡstudy. J Immunother Cancer, 2020, 8(1): e000367.
25. Favero F, Joshi T, Marquard AM, et al. Sequenza: Allele-specific copy number and mutation profiles from tumor sequencing data. Ann Oncol, 2015, 26(1): 64-70.
26. Yu G, Wang LG, Han Y, et al. ClusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
27. Xu S, Li X, Zhang H, et al. Frequent genetic alterations and their clinical significance in patients with thymic epithelial tumors. Front Oncol, 2021, 11: 667148.
28. Roden AC. Molecular changes are infrequent in thymic carcinomas but might represent targetable mutations. Mediastinum, 2017, 1: 23.
29. Hackman P, Vihola A, Haravuori H, et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet, 2002, 71(3): 492-500.
30. Han X, Chen J, Wang J, et al. TTN mutations predict a poor prognosis in patients with thyroid cancer. Biosci Rep, 2022, 42(7): BSR20221168.
31. Zheng QX, Wang J, Gu XY, et al. TTN-AS1 as a potential diagnostic and prognostic biomarker for multiple cancers. Biomed Pharmacother, 2021, 135: 111169.
32. Fang X, Zhong C, Weng S, et al. Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: Study protocol of a randomized, open-label, multicentric study. BMC Cancer, 2023, 23(1): 676.
33. Liu Z, Wang L, Guo C, et al. TTN/OBSCN 'Double-Hit' predicts favourable prognosis, 'immune-hot' subtype and potentially better immunotherapeutic efficacy in colorectal cancer. J Cell Mol Med, 2021, 25(7): 3239-3251.
34. Radovich M, Pickering CR, Felau I, et al. The integrated genomic landscape of thymic epithelial tumors. Cancer Cell, 2018, 33(2): 244-258.
35. Du H, Xie S, Guo W, et al. The prognostic value of tumor mutation burden and immune cell infiltration in thymic epithelial tumors. Ann Clin Lab Sci, 2021, 51(1): 44-54.
36. Prays J, Ortiz-Villalón C. Molecular landscape of thymic epithelial tumors. Semin Diagn Pathol, 2022, 39(2): 131-136.
37. Yang W, Chen S, Cheng X, et al. Characteristics of genomic mutations and signaling pathway alterations in thymic epithelial tumors. Ann Transl Med, 2021, 9(22): 1659.
38. Wang F, Wei XL, Wang FH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ⅰb/Ⅱ clinical trial NCT02915432. Ann Oncol, 2019, 30(9): 1479-1486.
39. Klempner SJ, Fabrizio D, Bane S, et al. Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: A review of current evidence. Oncologist, 2020, 25(1): e147-e159.
40. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.
41. Trabucco SE, Gowen K, Maund SL, et al. A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability-high cases in 67, 000 patient samples. J Mol Diagn, 2019, 21(6): 1053-1066.
42. Repetto M, Conforti F, Pirola S, et al. Thymic carcinoma with lynch syndrome or microsatellite instability, a rare entity responsive to immunotherapy. Eur J Cancer, 2021, 153: 162-167.
43. Mroz EA, Rocco JW. Intra-tumor heterogeneity in head and neck cancer and its clinical implications. World J Otorhinolaryngol Head Neck Surg, 2016, 2(2): 60-67.
44. McDonald KA, Kawaguchi T, Qi Q, et al. Tumor heterogeneity correlates with less immune response and worse survival in breast cancer patients. Ann Surg Oncol, 2019, 26(7): 2191-2199.
45. Nguyen L, WM Martens J, Van Hoeck A, et al. Pan-cancer landscape of homologous recombination deficiency. Nat Commun, 2020, 11(1): 5584.
46. Kim H, Ahn S, Kim H, et al. The prevalence of homologous recombination deficiency (HRD) in various solid tumors and the role of HRD as a single biomarker to immune checkpoint inhibitors. J Cancer Res Clin Oncol, 2022, 148(9): 2427-2435.
47. Rempel E, Kluck K, Beck S, et al. Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD). NPJ Precis Oncol, 2022, 6(1): 36.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Genomic analysis and biomarker discovery of thymic cancer based on whole exome sequencing: A retrospective cohort study

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