Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum

Sarasin, Alain; Quentin, Samuel; Droin, Nathalie; Sahbatou, Mourad; Saada, Véronique; Auger, Nathalie; Boursin, Yannick; Dessen, Philippe; Raimbault, Anna; Asnafi, Vahid; Schmutz, J.‐L.; Taı̈eb, Alain; Menck, Carlos Frederico Martins; Rosselli, Filippo; Rochelle, Laurianne Drieu La; Robert, Caroline; Fontbrune, Flore Sicre de; Sébert, Marie; Leblanc, Thierry; Kannouche, Patricia; Botton, Stéphane de; Solary, Éric; Soulier, Jean

doi:10.1182/blood-2019-01-895698

Cited by 38 publications

(41 citation statements)

References 19 publications

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“…Two recent studies reported a more than a thousand-fold increased risk of hematological malignancies in independent cohorts of XP-C patients 8,9 , which demonstrated mainly myelodysplastic syndrome with secondary acute myeloid leukemia manifestation. The genetic mechanism of increased risk of internal tumors in XP patients is not well understood.…”

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confidence: 99%

XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

et al. 2020

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Recent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). The genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyze a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observe a specific mutational pattern and an average of 25-fold increase of mutation rates in XP-C versus sporadic leukemia which we presume leads to its elevated incidence and early appearance. We describe a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients.

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XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

et al. 2020

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“…The c.1643_1644delTG deletion is a hotspot mutation in XPC 9,17,26–28 and a founder mutation in Northern Africa 16,27,29,30 . This variant co‐segregated with a high risk of developing haematological tumours in a few North African XP cases 28 . Interestingly, case 19P0 homozygous for this variant developed a high‐grade serous ovarian carcinoma at 27 years old.…”

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confidence: 99%

Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients

Santiago

Castro

Neto

et al. 2020

Acad Dermatol Venereol

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Background Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. Objectives To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. Methods Twenty-seven families were screened for germline variants in eight XP-related genes. Results All patients (N = 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/ XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. Conclusions We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.

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“…This study indicates that XPC-HR23B facilitated recognition of 8-oxoG in an OGG1-dependent BER. It is interesting to note that XP-C patients, in addition to high skin cancer rates, also have a higher incidence of internal cancer development (Giglia et al, 1998;Hollander et al, 2005;Sarasin et al, 2019). Thus, reduced kinetics of oxidatively generated DNA damage might be a major contributor to these internal cancers.…”

Section: Oxidatively Generated Base Damage Recognized By Ner Pathwaymentioning

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Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

et al. 2020

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Base and nucleotide excision repair (BER and NER) pathways are normally associated with removal of specific types of DNA damage: small base modifications (such as those induced by DNA oxidation) and bulky DNA lesions (such as those induced by ultraviolet or chemical carcinogens), respectively. However, growing evidence indicates that this scenario is much more complex and these pathways exchange proteins and cooperate with each other in the repair of specific lesions. In this review, we highlight studies discussing the involvement of NER in the repair of DNA damage induced by oxidative stress, and BER participating in the removal of bulky adducts on DNA. Adding to this complexity, UVA light experiments revealed that oxidative stress also causes protein oxidation, directly affecting proteins involved in both NER and BER. This reduces the cell's ability to repair DNA damage with deleterious implications to the cells, such as mutagenesis and cell death, and to the organisms, such as cancer and aging. Finally, an interactome of NER and BER proteins is presented, showing the strong connection between these pathways, indicating that further investigation may reveal new functions shared by them, and their cooperation in maintaining genome stability.

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Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum

Abstract: There is a Blood Commentary on this article in this issue.

Cited by 38 publications

References 19 publications

XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients

Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

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