Health supervision for people with Bloom syndrome

Cunniff, Christopher; Djavid, Amir Reza; Carrubba, Steven; Cohen, Bernard; Ellis, Nathan A.; Levy, Carolyn Fein; Jeong, Stacy; Lederman, Howard M.; Vogiatzi, Maria G; Walsh, Michael F.; Zauber, Ann G.

doi:10.1002/ajmg.a.40374

Cited by 44 publications

(62 citation statements)

References 33 publications

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“…The distribution of cancers in BS patients is similar to that of the general population but with a younger age onset with at least one third of BS patients developing a malignancy by the age of 25 and 80% by the age of 40 years (147). Among 144 BS patients, 223 cancers were reported (147).…”

Section: Bloom Syndrome (Bs)mentioning

confidence: 57%

“…BS, initially described by Dr. David Bloom in 1954 (145), is an autosomal recessive disorder caused by biallelic mutations in BLM located at 15q26.1 (146). As of 2018, almost 300 cases were known to the Bloom Syndrome Registry (147) with predominance of individuals of Eastern European descent, particularly within the Ashkenazi Jewish population who have an estimated carrier rate of 1 in 100 (148). BLM prevents erroneous HR during replication and resolves intermediate DNA structures such as displacement loops and double Holliday junctions (149).…”

Section: Bloom Syndrome (Bs)mentioning

confidence: 99%

“…BS neonates are small for gestational age with normal appearance with some exhibiting feeding difficulties resulting in failure to thrive (148). Photosensitive cutaneous rashes are among the most common manifestations that appear in infancy or early childhood and include telangiectasia erythema of the face (butterfly rash), hands, and forearms, as well as café-au-lait spots and hypopigmented macules (147). Immunodeficiency clinically manifests as frequent upper respiratory and gastrointestinal infections due to dysregulated T cells and hypogammaglobulinemia (particularly IgA and IgM deficiency) (150).…”

Section: Bloom Syndrome (Bs)mentioning

confidence: 99%

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DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

2020

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DNA damage response is essential to human physiology. A broad spectrum of pathologies are displayed by individuals carrying monoallelic or biallelic loss-of-function mutations in DNA damage repair genes. DNA repair syndromes with biallelic disturbance of essential DNA damage response pathways manifest early in life with multi-systemic involvement and a high propensity for hematologic and solid cancers, as well as bone marrow failure. In this review, we describe classic biallelic DNA repair cancer syndromes arising from faulty single-and double-strand DNA break repair, as well as dysfunctional DNA helicases. These clinical entities include xeroderma pigmentosum, constitutional mismatch repair deficiency, ataxia telangiectasia, Nijmegen breakage syndrome, deficiencies of DNA ligase IV, NHEJ/Cernunnos, and ERCC6L2, as well as Bloom, Werner, and Rothmund-Thompson syndromes. To give an in-depth understanding of these disorders, we provide historical overview and discuss the interplay between complex biology and heterogeneous clinical manifestations.

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Section: Bloom Syndrome (Bs)mentioning

confidence: 57%

Section: Bloom Syndrome (Bs)mentioning

confidence: 99%

Section: Bloom Syndrome (Bs)mentioning

confidence: 99%

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DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

2020

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“…Individuals with Bloom syndrome, unlike mice, survive embryogenesis but have developmental issues and a marked susceptibility to various types of cancers 63,64 . Our findings raise the possibility that impairing SWS1-SWSAP1-SPIDR function would suppress symptoms associated with Bloom syndrome.…”

Section: Discussionmentioning

confidence: 99%

Distinct pathways of homologous recombination controlled by the SWS1-SWSAP1-SPIDR complex

Prakash

Sandoval

Morati

et al. 2020

Preprint

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Homology-directed repair (HDR), a critical DNA repair pathway in mammalian cells, is complex, leading to multiple outcomes with different impacts on genomic integrity. However, the factors that control these different outcomes are often not well understood. Here we show that SWS1-SWSAP1-SPIDR controls distinct types of HDR. Despite their requirement for stable assembly of RAD51 recombinase at DNA damage sites, these proteins are not essential for intrachromosomal HDR, providing insight into why patients and mice with mutations are viable.However, SWS1-SWSAP1-SPIDR is critical for inter-homolog HDR, the first mitotic factor identified specifically for this function. Furthermore, SWS1-SWSAP1-SPIDR drives the high level of sister-chromatid exchange, promotes long-range loss of heterozygosity often involved with cancer initiation, and impels the poor growth of BLM helicase-deficient cells. The relevance of these genetic interactions is evident as SWSAP1 loss prolongs Blm-mutant embryo survival, suggesting a possible druggable target for the treatment of Bloom syndrome. MainDouble-strand breaks (DSBs) are among the most dangerous DNA lesions that can arise in cells and, if not repaired correctly, can lead to genomic instability and tumorigenesis 1 . Homologous recombination, also known as homology-directed repair (HDR), is the predominant pathway to repair DSBs in an error-free manner. The RAD51 recombinase plays a central role, whereby it forms filaments on single-stranded DNA at resected DNA ends through the activity of mediator proteins like BRCA2 2 and can be stabilized and/or remodeled by RAD51 paralogs, as shown for the yeast and worm proteins 3,4 . RAD51 nucleoprotein filaments subsequently invade a homologous template, typically the sister chromatid, to form a displacement loop (D loop), followed by repair synthesis. DNA helicases can unwind these D loops to promote HDR by the synthesis-dependent strand annealing pathway to result in noncrossovers. Alternatively, D loops that capture the other DNA end can mature into double Holliday junctions, which can be dissolved by BLM, a RECQ helicase deficient in individuals with Bloom syndrome, or resolved by structure-specific nucleases to form crossovers 5,6 . What controls the decision points for these various pathways is not well understood.SWS1-SWSAP1 is a recently identified complex that is critically important for HDR during meiosis in the mouse, promoting the stable assembly of both RAD51 and DMC1 nucleoprotein filaments at resected DNA ends in spermatocytes 7 . As a result, meiotic chromosomes in Sws1 and Swsap1 mutant mice often fail to synapse properly and mice are sterile. SWS1 homologs are readily

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“…Recently, PV/LPVs in genes coding RecQ helicases have been reported in patients with BC/OC [117,[246][247][248][249][250][251][252][253][254]. Interestingly, PV/LPVs in three of these genes are responsible for autosomal recessive genetic syndromes, all associated with an increased risk of malignancies: In fact, BLM, WRN, and RECL4 genes are the genetic cause of Bloom syndrome [255], Werner syndrome [256], and Rothmund-Thomson syndrome [257], respectively.…”

Section: Other Emerging Genesmentioning

confidence: 99%

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Angeli

Salvi

Tedaldi

2020

IJMS

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Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches. the recruitment of the recombinase RAD51 to the DNA double-strand breaks (DSBs) through the formation of a BRCA1-PALB2-BRCA2 complex. The BRCA2 protein contains a helical domain, three oligonucleotide binding domains, and a tower domain, which allow BRCA2 binding to both single-stranded DNA and double-stranded DNA [39,48,49].Germline PV/LPVs in the BRCA2 gene are associated with a 45-55% and 11-18% risk of developing BC and OC by the age of 70, respectively [20][21][22]. BRCA2 PV/LPVs have also been associated with an increased risk of BC in males, which is estimated at 6.8% by the age of 70 [43]. In addition, BRCA2 PV/LPVs have been associated with an increased risk of prostate cancer [50], pancreatic cancer [47,51], and uveal melanoma [52,53].According to the National Comprehensive Cancer Network (NCCN) guidelines, women with BRCA1/2 PV/LPVs should undergo a surveillance protocol, including clinical breast examination every 6-12 months and annual breast magnetic resonance imaging (MRI), starting at the age of 25, annual mammography with consideration of tomosynthesis, starting at the age of 30, and annual transvaginal ultrasound and serum CA-125 concentration, although of uncertain benefit, beginning at age 30-35 years [54]. Moreover, they should evaluate the opportunity of a bilateral risk-reducing mastectomy (RRM) and of a bilateral risk-reducing salpingo-oophorectomy (RRSO), typically at between 35 and 40 years and upon completion of childbearing [54]. Men with BRCA1/2 PV/LPVs should undergo clinical breast examination every 6-12 months, starting at the age of 35, and annual prostate cancer screening, starting at the age of 40 (in particular in BRCA2 PV/LPV carriers) [55]. In both sexes, screening for melanoma and pancreatic cancer should be evaluated on the basis of family...

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Health supervision for people with Bloom syndrome

Cited by 44 publications

References 33 publications

DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

Distinct pathways of homologous recombination controlled by the SWS1-SWSAP1-SPIDR complex

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

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