Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Decreases Risk of Childhood Acute Lymphoblastic Leukemia (ALL): A Study of the Chinese and Malay Population.
Authors: Kham Shirley Kow Yin , Foo Toon Chai , Hany Ariffin , Chan Yiong Huak , Lin Hai Peng , Quah Thuan Chong , Yeoh Allen Eng Juh 
Published: October 2019

Abstract
MTHFR plays a key role in folate metabolism by shuttling one-carbon units between nucleotide synthesis and methylation reactions. Two frequent polymorphisms in the human MTHFR gene (C677T and A1298C) confer moderate functional impairment of MTHFR activity for homozygous mutant individuals. These polymorphisms have been inconclusively shown to confer some form of protection against development of cancer. We postulate that MTHFR polymorphisms influence risk of developing childhood ALL by comparing the frequency of these polymorphisms in normal controls and children with ALL in their specific races. As the frequencies of these polymorphisms are unknown in Chinese and Malays populations, we performed a population study among Chinese and Malay populations, and children with ALL. A total of 310 childhood ALL were enrolled between 1992–2005 (NUH-ALL 92, HK-ALL 98, MASPORE-ALL 2003). The cases comprise of 202 Chinese ALL (B-lineage=180, T-lineage=15, infant=7) and 108 Malay ALL (B-lineage=98, T-lineage=3, infant=7). A total of 231 cases (Ch=144, Mal=87) were screened for TEL-AML1 and MLL rearrangements using RT-PCR. Umblical cord bloods (anonymous) were used as controls. Genotyping was carried out using PCR/RFLP. The frequencies of MTHFR polymorphisms were distinctly different among the Chinese and Malay populations. 54.2% of the Chinese population was either heterozygous (45%) or homozygous (9.2%) for MTHFR C677T while only 25.5% of the Malay population were either heterozygous (23.9%) or homozygous (1.6%). The frequency of MTHFR C677T polymorphism among the ALL patients were significantly different from the normal population (Chinese p=0.01, Malay p= 0.068). Specifically, the frequencies of heterozygous and homozygous for C677T among ALL patients were lower compared to the normal population: Chinese ALL 33.7% and 8.9%; Malays ALL 15.7% and 1%. The protection against childhood ALL seems to be conferred to reducing the risk of developing TEL-AML1 subtype (Table 2). This may explain the reason why the frequency of TEL-AML1 subtype is lower among the Chinese compared to the Malays (24/144 [16.7%] Chinese vs 22/87 [25.3%] Malays). No significant association of MTHFR A1298C with risk of childhood ALL. Our findings suggested that MTHFR C677T significantly reduces the risk of developing childhood leukaemia especially those with onset in utero.
Table 1: Frequency of the MTHFR C677T genotypes in childhood ALL and controls (A) Chinese Genotype Controls (n=262) ALL (n=202) OR(95%CI) p CC 119(45.4%) 116(57.4%) 1.0(referent) - CT or TT 143(54.2%) 86(42.6%) 1.6(1.1–2.3) 0.01 (B) Malays Controls(n=251) ALL(n=108) CC 187(74.5%) 90(83.3%) 1.0(referent) - CT or TT 64(25.5%) 18(16.7%) - 0.068 Table 2: Distribution of MTHFR C677T genotypes in the 3 subgroups. (A) Chinese Controls TEL-AML1 or MLL TEL-AML1 or MLL Hyperdiploidy Non-hyperderploidy Genotype (n=262) Present(n=32; MLL=8/32) Absent(n=112) (n=22) (n=50) CC 119(45.4%) 19(59.3%) 62(55.4%) 16(72.7%) 26(52%) CT or TT 143(54.2%) 13(40.6%) p=0.045 50(44.7%) p=0.129 6(27.3%) p<0.0001 24(48%) p=0.24 (B) Malays Genotype Controls(n=251) Present(n=26; MLL=4/26) Absent(n=61) CC 187(74.5%) 24(92.3%) 48(78.7%) No Data No Data CT or TT 64(25.5%) 2(7.7%) p=0.001 13(21.3%) p=0.27