Cancer risk among RECQL4 heterozygotes

Martin-Giacalone, Bailey A.; Rideau, Ta-Tara; Scheurer, Michael E.; Lupo, Philip J.; Wang, Lisa L.

doi:10.1016/j.cancergen.2022.02.001

Cited by 6 publications

(3 citation statements)

References 19 publications

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“…Homozygous or compound heterozygous germline mutations in the RECQL4 gene are linked to the recessive syndromes Rapadilino syndrome (RAPADILINO syndrome; OMIM #266280) and Baller–Gerold syndrome (BGS; OMIM #218600). Recent work investigating the cancer risk in a cohort of 123 individuals with heterozygous germline RECQL4 mutations showed that the prevalence of cancer was not increased in these patients but that patients with type II Rothmund–Thomson syndrome with biallelic REC mutations (including RECQL4 ) were specifically at increased risk of developing lymphomas and osteosarcomas [ 35 ]. Another member of the Rec family, WRN , is associated with Werner syndrome (WS; OMIM #277700) and increases the risk of thyroid carcinoma, melanoma, breast cancer and meningioma as well as soft tissue and bone sarcomas [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Al Saati,

Vande Perre,

Plenecassagnes

et al. 2023

IJMS

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Even though male breast cancer (MBC) risk encompasses both genetic and environmental aetiologies, the primary risk factor is a germline pathogenic variant (PV) or likely pathogenic variant (LPV) in BRCA2, BRCA1 and/or PALB2 genes. To identify new potential MBC-specific predisposition genes, we sequenced a panel of 585 carcinogenesis genes in an MBC cohort without BRCA1/BRCA2/PALB2 PV/LPV. We identified 14 genes carrying rare PVs/LPVs in the MBC population versus noncancer non-Finnish European men, predominantly coding for DNA repair and maintenance of genomic stability proteins. We identified for the first time PVs/LPVs in PRCC (pre-mRNA processing), HOXA9 (transcription regulation), RECQL4 and WRN (maintenance of genomic stability) as well as in genes involved in other cellular processes. To study the specificity of this MBC PV/LPV profile, we examined whether variants in the same genes could be detected in a female breast cancer (FBC) cohort without BRCA1/BRCA2/PALB2 PV/LPV. Only 5/109 women (4.6%) carried a PV/LPV versus 18/85 men (21.2%) on these genes. FBC did not carry any PV/LPV on 11 of these genes. Although 5.9% of the MBC cohort carried PVs/LPVs in PALLD and ERCC2, neither of these genes were altered in our FBC cohort. Our data suggest that in addition to BRCA1/BRCA2/PALB2, other genes involved in DNA repair/maintenance or genomic stability as well as cell adhesion may form a specific MBC PV/LPV signature.

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Section: Discussionmentioning

confidence: 99%

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Al Saati,

Vande Perre,

Plenecassagnes

et al. 2023

IJMS

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“…However, it was reported that cancer risk for individuals with monoallelic RECQL4 pathogenic variants was not significantly different with estimates obtained from SEER data. 22 Although RECQL4 germline mutations also promote hereditary predisposition and familial clustering of hematopoietic neoplasms such as MDS, leukemia, and lymphoma, 23 the incidence is relatively rare. We summarized hematological malignancies in RTS patients which might be in association with specific mutational sites of RECQL4 (Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

De novo myelodysplastic syndrome in a Rothmund-Thomson Syndrome patient with novel pathogenic RECQL4 variants

et al. 2023

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Rothmund-Thomson syndrome (RTS) is a rare autosomal-recessive disorder with clinical features consisting of rash, poikiloderma, sparse hair, short stature, juvenile cataracts, skeletal abnormalities, and cancer predisposition. Genetic studies involving detection of pathogenic RECQL4 variants provide the diagnostic certitude. Osteosarcoma was found in two-thirds RECQL4-mutated RTS patients, while hematological malignancies were rarely reported. The variant diversity of RECQL4 gene has not been fully identified and mutations associated with hematologic malignancies are not well described. In this study, we presented a pedigree of RTS from a Chinese family, among which the proband was diagnosed with de novo myelodysplastic syndrome (MDS). Comprehensive medical examination and chromosome karyotyping were performed on the proband. Whole exome sequencing (WES) was performed on the proband, his sister and his mother. The familial cosegregation of sequence variants derived from WES was conducted by polymerase chain reaction–based Sanger sequencing. Structures of candidate RECQL4 mutants were done by in silico analysis to assess pathogenicity. Three novel RECQL4 germline variants, including c.T274C, c.G3014A, and c.G801C, were identified by WES and validated by Sanger sequencing. Prediction of conformation indicated that the structural stability of human RECQL4 protein was largely affected with these variants. The co-occurring U2AF1 p.S34F and TP53 p.Y220C mutations might contribute to the development of MDS. Our study expands the mutational spectrum of RECQL4 and provides underlying molecular mechanism for the development of MDS in RTS patients.

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“…A recent study examined the prevalence of cancer risk in patients carrying monoallelic pathogenic variants in the RECQL4 gene ( Martin-Giacalone et al, 2022 ). Despite some data suggesting that heterozygous germline variants in RECQL4 increase risk of osteosarcoma, in this analysis of an international registry of RTS II patients and their family members, investigators found that RTS II family members with heterozygous germline pathogenic variant in RECQL4 did not have an increased risk of developing cancer, compared to the age-adjusted population estimate per the Surveillance, Epidemiology, and End Results (SEER) program ( Maciaszek et al, 2019 ; Martin-Giacalone et al, 2022 ).…”

Section: Overview Of Dna Recq Helicases In Cancermentioning

confidence: 99%

RecQ Helicase Somatic Alterations in Cancer

Thakkar

Lee²,

Meyer³

et al. 2022

Front. Mol. Biosci.

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Named the “caretakers” of the genome, RecQ helicases function in several pathways to maintain genomic stability and repair DNA. This highly conserved family of enzymes consist of five different proteins in humans: RECQL1, BLM, WRN, RECQL4, and RECQL5. Biallelic germline mutations in BLM, WRN, and RECQL4 have been linked to rare cancer-predisposing syndromes. Emerging research has also implicated somatic alterations in RecQ helicases in a variety of cancers, including hematological malignancies, breast cancer, osteosarcoma, amongst others. These alterations in RecQ helicases, particularly overexpression, may lead to increased resistance of cancer cells to conventional chemotherapy. Downregulation of these proteins may allow for increased sensitivity to chemotherapy, and, therefore, may be important therapeutic targets. Here we provide a comprehensive review of our current understanding of the role of RecQ DNA helicases in cancer and discuss the potential therapeutic opportunities in targeting these helicases.

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Cancer risk among RECQL4 heterozygotes

Cited by 6 publications

References 19 publications

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

De novo myelodysplastic syndrome in a Rothmund-Thomson Syndrome patient with novel pathogenic RECQL4 variants

RecQ Helicase Somatic Alterations in Cancer

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