Unraveling the genetic architecture of hepatoblastoma risk: birth defects and increased burden of germline damaging variants in gastrointestinal/renal cancer predisposition and DNA repair genes

The ultrarare hepatoblastoma is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Pathogenic or likely pathogenic variants mapped to 10 cancer predisposition genes (APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL,) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several damaging rare variants mapped to genes impacting liver functions were observed. To our knowledge, this is the first comprehensive assessment of rare germline variants in HB patients, contributing to elucidating the genetic architecture of HB risk.

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

JNCI Cancer Spectrum ◽

10.1093/jncics/pky054 ◽

2018 ◽

Vol 2 (4) ◽

Cited By ~ 5

Author(s):

Ming Ren Toh ◽

Jian Bang Chiang ◽

Siao Ting Chong ◽

Sock Hoai Chan ◽

Nur Diana Binte Ishak ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Cancer Predisposition ◽

Colorectal Cancers ◽

Dna Repair Genes ◽

Young Onset ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Repair Genes

Abstract 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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Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-17-0319 ◽

2017 ◽

Vol 27 (3) ◽

pp. 285-294 ◽

Cited By ~ 7

Author(s):

Jason E. Sandler ◽

Huang Huang ◽

Nan Zhao ◽

Weiwei Wu ◽

Fangfang Liu ◽

...

Keyword(s):

Dna Repair ◽

Thyroid Cancer ◽

Dna Repair Genes ◽

Germline Variants ◽

Diagnostic Radiation ◽

Repair Genes

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Correction: Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

British Journal of Cancer ◽

10.1038/s41416-019-0419-4 ◽

2019 ◽

Vol 120 (8) ◽

pp. 867-867

Author(s):

Martina Mijuskovic ◽

Edward J. Saunders ◽

Daniel A. Leongamornlert ◽

Sarah Wakerell ◽

Ian Whitmore ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Cancer Patients ◽

Metastatic Disease ◽

Dna Repair Genes ◽

Germline Variants ◽

Repair Genes ◽

Angiogenesis Pathway

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Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Genes ◽

10.3390/genes11030314 ◽

2020 ◽

Vol 11 (3) ◽

pp. 314 ◽

Cited By ~ 2

Author(s):

Tommi Rantapero ◽

Tiina Wahlfors ◽

Anna Kähler ◽

Christina Hultman ◽

Johan Lindberg ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Dna Repair Genes ◽

Carrier Rate ◽

Single Nucleotide Variants ◽

Repair Gene ◽

Germline Variants ◽

Dna Repair Gene ◽

Significant Difference ◽

Repair Genes

Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with CHEK2 (4.1%) and ATM (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed (p = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.

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