Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer

Abstract

Several known breast cancer susceptibility genes with moderate-to-high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein-truncating variants, and the role of rare missense mutations has remained poorly addressed. To identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious. Thirty-five variants were studied here for the disease association using Finnish breast cancer case (n = 492-2,035) and control (n = 277-1,539) cohorts. As a result, two missense variants in genes involved in DNA replication, RECQL p.I156M and POLG p.L392V, the former involving genomic and the latter mitochondrial DNA replication, showed significant association with risk of breast cancer. Rare RECQL p.I156M allele was observed in breast cancer cases only (6/1,946, 0.3%, p = 0.043), whereas POLG p.L392V was two times more frequent in breast cancer cases (53/2,238, 2.4%) compared to controls (18/1,539, 1.2%, OR = 2.1, 95% CI 1.2-3.5, p = 0.010). Based on the current genetic data, both RECQL p.I156M and POLG p.L392V represent novel breast cancer predisposing alleles.

Deoxyribonucleotide Triphosphate Metabolism in Cancer and Metabolic Disease

“…Maintenance of mitochondrial dNTP pools is critical for proper mtDNA function. Alterations in nuclear genes involved in transport of cytosolic dNTPs (e.g., SLC25A4), the salvage nucleotide biosynthesis in the inner mitochondrial membrane (e.g., TK2 and DGUOK), and genes involved in mtDNA replication (e.g., TWNK and POLG) are implicated in both cancer and metabolic syndromes ( 63 , 68 , 77 – 79 , 130 – 133 ). Moreover, dysfunction in the electron transport chain induces oxidative stress, which has been associated with impaired one-carbon metabolism ( 134 , 135 ), an essential anapleurotic pathway for both purine and pyrimidine nucleotides.…”

Characteristics and outcome of patients with acute myeloid leukaemia and t(8;16)(p11;p13): results from an International Collaborative Study*

“…Besides well‐described mutations in AML, we found mutations in POLG , which is responsible for mitochondrial DNA replication 47 as well as mutations in MLH1 , which belongs to the DNA mismatch repair system and plays an important role in maintaining genomic stability 48–52 . Whereas both mutations were described to increase the risk of hereditary and sporadic cancers, 48,50,52,53 their incidence and clinical impact in AML are less well defined. Both mutations were not described by Ley et al ., who performed WGS or whole‐exome sequencing on 200 adult, de novo AML patients, along with RNA and microRNA sequencing and DNA‐methylation analysis 54 .…”

RecQ Helicase Somatic Alterations in Cancer

“…There are conflicting studies investigating germline variants in RECQL1 as a cancer susceptibility gene. Germline missense, truncating, and splice site variants in RECQL1 have been enriched in participants with breast cancer in five different ethnic groups ( Cybulski et al, 2015 ; Sun et al, 2015 ; Kwong et al, 2016 ; Sun et al, 2017 ; Tervasmaki et al, 2018 ). However, there have been a few subsequent studies with conflicting evidence, such that RECQL1 appears to be a moderate breast cancer risk gene that needs further study ( Bogdanova et al, 2017 ; Li et al, 2018a ; Nguyen-Dumont et al, 2018 ).…”