The Role of BRCA1 and BRCA2 Genes in the Appearance of Pediatric and Adolescent Disorders

Drikos, Ioannis; Sachinidis, Alexandros; Vassi, Ioanna; Boutou, Effrossyni

doi:10.21767/2576-3903.100015

Cited by 2 publications

(2 citation statements)

References 44 publications

(63 reference statements)

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“…A homozygous nonsense variant in NTHL1 (p.Gln90*) was detected among seven CRC patients from three unrelated families whereas compound heterozygous NTHL1 variants were found in a patient with multiple primary tumors, including CRC (38). For WRN , which encoded for a helicase with exonuclease function, preliminary studies hinted at the possibility of WRN-BRCA1 interaction in HR pathway (39). Pathogenic variants in WRN were predominantly truncating and WRN somatic hypermethylation was also observed in various tumors, including colon tumors (40).…”

Section: Discussionmentioning

confidence: 99%

Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer

Toh

Chiang

Chong

et al. 2018

JNCI Cancer Spectrum

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Background Growing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer. Methods We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells. Results In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C>T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation. Conclusion A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.

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Section: Discussionmentioning

confidence: 99%

Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer

Toh

Chiang

Chong

et al. 2018

JNCI Cancer Spectrum

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“…The BRCA1 mutations may alter BRCA1 localization and restrict the protein out of the core. Two of the Cterminal mutations (M1775R and Y1853X) restrict nuclear localization disrupt the folding of the C-terminal of BRCA1 [7][8][9], suggesting that the conformation changes they cause may be detrimental to BRCA1 nuclear transport [6,10].…”

Section: Introductionmentioning

confidence: 99%

The Impact of M1775K Variant in BRCA1 Regulation

Drikos¹,

Boutou²

2017

Transl Med

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The missense mutations of the BRCT domain of human BRCA1 have been argued to be associated with predisposition to hereditary breast/ovarian cancer. Mutations at the C-terminus of the protein are critical for function and structural excellence. This mutation has been associated with changes in the structure of the protein and loss of interaction with other peptides involved in cell cycle control. In previous studies we have shown that the modification of various mutants in BRCT domain, such as Met1775K is strongly affecting the functional and structural integrity of the domain and the binding affinity with phospopeptides.In the present study we have attempted to determine the effect of the M1775K mutation on the intracellular localization of the protein. For this purpose, GFPBRCA1-BRCT M1775K mutant was created and expressed in MCF-7 cell lines. Due to fluorescence microscopy determined that the mutation affects the protein's mislocalization in relation to wtBRCA1-BRCT protein. Mutant EGFP-BRCA1-BRCT M1775K form is mainly determined in the cytoplasm in contrast to the EGFPwtBRCA1-BRCT protein that localizes into nucleus and cytoplasm.Cytoplasmic mislocalization of M1775K mutation, presented here, may be related to disruption of BRCA1-BRCT folding. The M1775K mutation influences the nuclear transport of BRCA1-BRCT domain to the nucleus, suggesting that the impact of the integrity of the BRCA1-BRCT domain is crucial in functional and structural level.

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The Role of BRCA1 and BRCA2 Genes in the Appearance of Pediatric and Adolescent Disorders

Cited by 2 publications

References 44 publications

Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer

Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer

The Impact of M1775K Variant in BRCA1 Regulation

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