Biallelic MUTYH gene mutation resulting in fluoropyrimidine-resistant advanced rectal cancer: A case report

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide and the third most common cancer in Thailand. Approximately 2% - 5% of CRC cases are associated with inherited cancer syndromes, whereas the majority is sporadic. Herein, we have reported the case of a 32-year-old male with poorly differentiated middle rectal adenocarcinoma (T4bN1M1, Stage IV) that was refractory to fluoropyrimidine-based chemotherapy. Genetic profiling revealed a homozygous c.934-2A>G mutation in the MUTYH gene, which disrupted the DNA repair. Despite palliative radiation (30 Gy in 10 fractions) and systemic therapies (capecitabine plus oxaliplatin + panitumumab and fluorouracil, leucovorin, and irinotecan + bevacizumab), the disease progressed rapidly. Third-line therapy with Irinotecan plus oxaliplatin demonstrated initial success (partial response). Eventually, disease progression ensued. This report highlights the challenges of managing CRC caused by biallelic MUTYH mutations and emphasizes the importance of comprehensive genomic profiling for guiding therapeutic decisions. A review of similar cases in the literature is also presented.

Keywords

Colorectal neoplasms / Colonic neoplasms / Rectal neoplasms / Colorectal neoplasms / Hereditary non-polyposis / Antineoplastic agents / MUTYH

Funding

None.

Conflict of interest

The authors declare they have no competing interests.

References

[1] Sung H, Ferlay J, Siegel RL, et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71:209-249. doi: 10.3322/caac.21660

[2] Jasperson KW, Tuohy TM, Neklason DW, Burt RW.Hereditary and familial colon cancer. Gastroenterology. 2010; 138:2044-2058. doi: 10.1053/j.gastro.2010.01.054

[3] Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: History, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009; 76:1-18. doi: 10.1111/j.1399-0004.2009.01230.x

[4] Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999; 116:1453-1456. doi: 10.1016/s0016-5085(99)70510-x

[5] Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-268. doi: 10.1093/jnci/djh034

[6] Nagy R, Sweet K, Eng C.Highly penetrant hereditary cancer syndromes. Oncogene. 2004; 23:6445-6470. doi: 10.1038/sj.onc.1207714

[7] Takao M, Zhang QM, Yonei S, Yasui A. Differential subcellular localization of human MutY homolog (hMYH) and the functional activity of adenine:8-oxoguanine DNA glycosylase. Nucleic Acids Res. 1999;27:3638-3644. doi: 10.1093/nar/27.18.3638

[8] Shinmura K, Yamaguchi S, Saitoh T, et al. Adenine excisional repair function of MYH protein on the adenine:8- hydroxyguanine base pair in double-stranded DNA. Nucleic Acids Res. 2000;28:4912-4918. doi: 10.1093/nar/28.24.4912

[9] Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol. 2009; 27:3975-3980. doi: 10.1200/JCO.2008.21.6853

[10] Slupska MM, Baikalov C, Luther WM, Chiang JH, Wei YF, Miller JH. Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J Bacteriol. 1996; 178:3885-3892. doi: 10.1128/jb.178.13.3885-3892.1996

[11] Ohtsubo T, Nishioka K, Imaiso Y, et al. Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. Nucleic Acids Res. 2000;28:1355-1364. doi: 10.1093/nar/28.6.1355

[12] Jones S, Lambert S, Williams GT, Best JM, Sampson JR, Cheadle JP. Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas. Br J Cancer. 2004; 90:1591-1593. doi: 10.1038/sj.bjc.6601747

[13] Nielsen M, de Miranda NF, van Puijenbroek M, et al. Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas. BMC Cancer. 2009;9:184. doi: 10.1186/1471-2407-9-184

[14] Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008; 26: 2006-2012. doi: 10.1200/JCO.2007.14.9898

[15] Ducreux M, Bennouna J, Hebbar M, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011; 128:682-690. doi: 10.1002/ijc.25369

[16] Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: Randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014;25:1346-1355. doi: 10.1093/annonc/mdu141

[17] Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol. 2010; 28:4697-4705. doi: 10.1200/JCO.2009.27.4860

[18] Beretta GD, Petrelli F, Stinco S, et al. FOLFIRI+bevacizumab as second-line therapy for metastatic colorectal cancer pretreated with oxaliplatin: A pooled analysis of published trials. Med Oncol. 2013;30:486. doi: 10.1007/s12032-013-0486-y

[19] Jo H, Lee MS, Lee YP, et al. A comparison of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab and FOLFIRI plus aflibercept as second-line treatment for metastatic colorectal cancer. Clin Oncol (R Coll Radiol). 2022;34:e323-e328. doi: 10.1016/j.clon.2022.02.011

[20] Iwamoto S, Takahashi T, Tamagawa H, et al. FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: The randomized phase III EAGLE study. Ann Oncol. 2015;26:1427-1433. doi: 10.1093/annonc/mdv197

[21] Information NCfB. ClinVar; [VCV000041766.57]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000041766.57 [2023 Jun 02]

[22] Haller DG, Rothenberg ML, Wong AO, et al. Oxaliplatin plus irinotecan compared with irinotecan alone as second-secondline treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008;26: 4544-4550.doi: 10.1200/JCO.2007.14.9898

[23] Cleary SP, Cotterchio M, Jenkins MA, et al. Germline MutY human homologue mutations and colorectal cancer: A multisite case-control study. Gastroenterology. 2009; 136:1251-1260. doi: 10.1053/j.gastro.2008.12.050

[24] Ali M, Kim H, Cleary S, Cupples C, Gallinger S, Bristow R. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008; 135:499-507. doi: 10.1053/j.gastro.2008.04.035

[25] Taki K, Sato Y, Nomura S, et al. Mutation analysis of MUTYH in Japanese colorectal adenomatous polyposis patients. Fam Cancer. 2016;15:261-265. doi: 10.1007/s10689-015-9857-1

[26] Thibodeau ML, Zhao EY, Reisle C, et al. Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis. Cold Spring Harb Mol Case Stud. 2019;5:a003681. doi: 10.1101/mcs.a003681

[27] Tao H, Shinmura K, Hanaoka T, et al. A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus. Carcinogenesis. 2004;25:1859-1866. doi: 10.1093/carcin/bgh206

[28] Miyaki M, Iijima T, Yamaguchi T, et al. Germline mutations of the MYH gene in Japanese patients with multiple colorectal adenomas. Mutat Res. 2005; 578:430-433. doi: 10.1016/j.mrfmmm.2005.01.017

[29] Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003;362:39-41. doi: 10.1016/S0140-6736(03)13805-6