Human pathology · 2025
Identification of constitutional MLH1 methylation in MLH1-deficient colorectal cancer.
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Wang Jun, Zhang Zijuan, Liu Hangqi, Wang Jing, Cai Yumeng, Zhang Yuhan, Chen Longyun, Wu Huanwen, Liang Zhiyong
Аннотация
BACKGROUND: Constitutional MLH1 methylation (epimutation), a poorly recognized mechanism for Lynch syndrome (LS), is usually overlooked due to current screening strategies that rely on tumor MLH1 methylation as an indication of sporadic mismatch repair-deficient (dMMR) colorectal cancer (CRC). We aimed to assess the frequency and clinicopathological characteristics of constitutional MLH1 methylation among dMMR CRC cases with tumor MLH1 methylation.
METHODS: We conducted a retrospective study on two independent cohorts: a discovery cohort of 48 MLH1-deficient CRC cases (2017-2021) and a validation cohort of 159 consecutive CRC cases (2022-2024). Real-time methylation-specific PCR (qMSP) screened for tumor MLH1 methylation, followed by constitutional MLH1 methylation testing on paired normal colorectal mucosa (NCM) DNA, confirmed by CpG pyrosequencing.
RESULTS: In the discovery cohort, constitutional MLH1 methylation was identified in 4 of 31 individuals (12.9 %) with tumor MLH1 methylation, including 2 with high-level and 2 with low-level mosaic methylation. These patients were generally younger (median age: 56 years) , and three of the four tested negative for the BRAF V600E mutation. When applying an age threshold of ≤55 years, the highest positivity rate for constitutional MLH1 methylation was achieved at 2 of 4 (50.0 %), and notably, both exhibited relatively high-level epimutations. A refined screening strategy specially targeting high-level constitutional MLH1 methylation was developed. In the validation cohort, 35 MLH1-deficient, BRAF V600E-negative cases were tested, including 18 individuals aged ≤55 years and 17 randomly selected controls aged >55 years. Constitutional MLH1 methylation was successfully identified in one patient from the younger group, while none was detected among the older controls. All five cases lacked a significant family history, and one patient developed three LS-associated cancers. In addition, heterogeneous MMR protein expression patterns, and early partial MLH1/PMS2 loss in precancerous lesions were observed.
CONCLUSIONS: Our findings highlight a subset of younger patients with constitutional MLH1 methylation among MLH1-deficient, MLH1-methylated CRC cases. Patients aged ≤55 years, whose tumors exhibit MLH1 methylation or lack the BRAF V600E mutation, are recommended to undergo additional testing for constitutional MLH1 methylation to improve LS-related clinical management.
METHODS: We conducted a retrospective study on two independent cohorts: a discovery cohort of 48 MLH1-deficient CRC cases (2017-2021) and a validation cohort of 159 consecutive CRC cases (2022-2024). Real-time methylation-specific PCR (qMSP) screened for tumor MLH1 methylation, followed by constitutional MLH1 methylation testing on paired normal colorectal mucosa (NCM) DNA, confirmed by CpG pyrosequencing.
RESULTS: In the discovery cohort, constitutional MLH1 methylation was identified in 4 of 31 individuals (12.9 %) with tumor MLH1 methylation, including 2 with high-level and 2 with low-level mosaic methylation. These patients were generally younger (median age: 56 years) , and three of the four tested negative for the BRAF V600E mutation. When applying an age threshold of ≤55 years, the highest positivity rate for constitutional MLH1 methylation was achieved at 2 of 4 (50.0 %), and notably, both exhibited relatively high-level epimutations. A refined screening strategy specially targeting high-level constitutional MLH1 methylation was developed. In the validation cohort, 35 MLH1-deficient, BRAF V600E-negative cases were tested, including 18 individuals aged ≤55 years and 17 randomly selected controls aged >55 years. Constitutional MLH1 methylation was successfully identified in one patient from the younger group, while none was detected among the older controls. All five cases lacked a significant family history, and one patient developed three LS-associated cancers. In addition, heterogeneous MMR protein expression patterns, and early partial MLH1/PMS2 loss in precancerous lesions were observed.
CONCLUSIONS: Our findings highlight a subset of younger patients with constitutional MLH1 methylation among MLH1-deficient, MLH1-methylated CRC cases. Patients aged ≤55 years, whose tumors exhibit MLH1 methylation or lack the BRAF V600E mutation, are recommended to undergo additional testing for constitutional MLH1 methylation to improve LS-related clinical management.