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Tumor Discovery MUTYH mutation in advanced rectal cancer with 5-FU resistance

caused by biallelic mutations in the MUTYH gene, which Figure 1), the carcinoembryonic antigen (CEA) levels
encodes a DNA glycosylase that is essential for oxidative increased tenfold, from 2.93 to 102.54 ng/dL. Furthermore,
damage repair. 7,8 CT imaging revealed multiple liver metastases (Figure 2).
MUTYH mutations are associated with an increased Second-line therapy with fluorouracil, leucovorin, and
9
risk of CRC. However, their clinical significance remains irinotecan (FOLFIRI) was administered in addition to
uncertain. 10,11 Variants such as c.934-2A>G, which have bevacizumab. 18-20 Disease progression, in the form of new
been identified predominantly in Asian populations, may lung metastases, was observed after 2 months. The CEA
disrupt splicing and impair the DNA repair function of the level increased to 860.32 ng/dL. Comprehensive genomic
MUTYH gene. 12,13 profiling revealed a homozygous c.934-2A>G MUTYH
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Herein, we report the case of a young Thai male with mutation. This variant, which is linked to altered splicing,
advanced rectal cancer who harbored a homozygous c.934- is associated with disrupted DNA repair. There were no
2A>G mutation, while emphasizing the mutation’s clinical mutations of the MLH1, MSH2, MSH3, MSH6, PMS2,
relevance and implications for treatment. APC, PTEN, ATM, AXIN2, STK11, SMAD4, TP53, CDH1,
CHEK2, and EPCAM genes.
2. Case presentation Third-line treatment with irinotecan and oxaliplatin

A 32-year-old Thai male presented with recurrent urinary tract (IROX) led to a partial response, with CEA levels
22
infections and sepsis caused by Escherichia coli. Computed decreasing to 27.71 ng/mL after the fourth cycle and
tomography (CT) imaging revealed a 10-cm ulcerated rectal improved performance status. However, oxaliplatin
mass invading the urinary bladder. Colonoscopy confirmed hypersensitivity limited the treatment to eight cycles. After
the presence of poorly differentiated adenocarcinoma, 16 months of stable disease, progression was observed in
which exhibited positive immunohistochemical staining for the form of new metastatic lesions. The patient declined
CK20 and CDX2 and negative staining for CK7. Molecular further systemic therapy and transitioned to end-of-
testing revealed wild-type BRAF, KRAS, and NRAS genes life care. He passed away peacefully just 1 month period
and a proficient MMR status, excluding LS. The patient after the disease progression. He cannot fit for the 4 -line
th
was diagnosed with rectal cancer and the TNM stage of the treatment of regorafenib.
tumor was T4bN1M1 (Stage IV).
Given the advanced stage of the tumor, the 3. Discussion
multidisciplinary tumor board advised palliative colostomy MUTYH was first described in 2002 and is on the
and administration of radiation therapy (30 Gy in 10 chromosome 1p34.3-1p32.1. The gene encodes a
fractions) to alleviate the symptoms. First-line treatment DNA glycosylase that is crucial for repairing oxidative
with capecitabine plus oxaliplatin (CAPOX) 14,15 and damage. 23,24 Biallelic mutations in MUTYH lead to MAP,
panitumumab 16,17 was initiated. Despite the administration which is characterized by multiple adenomas and an
of four chemotherapy cycles (each lasting 3 weeks; elevated risk of CRC. In Asian populations, variants such

Figure 1. The patient’s treatment timeline. In late 2020, the patient was diagnosed with advanced rectal cancer, and he underwent a palliative colostomy to
prevent obstruction and radiation. The first-line treatment included CAPOX and panitumumab. The second-line therapy included FOLFIRI and bevacizumab.
Both lines of treatment were ineffective within the first 2 months. The third line of treatment, which included IROX, was highly effective. In addition, a
homozygous MUTYH gene mutation was detected. The patient responded well to this treatment for 16 months. Subsequently, the disease progressed. End-
of-life care was initiated as the patient refused further treatment. The patient eventually passed away 1 month after the cessation of chemotherapy.
Abbreviations: CA: Cancer; CAPOX: Capecitabine plus oxaliplatin; Fr: Fractions; FOLFIRI: Fluorouracil, leucovorin, and irinotecan; Gy; Gray;
IROX: Irinotecan plus oxaliplatin; PD: Progression of disease; PFS: Progression-free survival; RT: Radiation therapy.

Volume 4 Issue 1 (2025) 121 doi: 10.36922/td.5164