The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers

Laitman, Yael; Boker-Keinan, Lital; Berkenstadt, Michal; Liphsitz, Irena; Weissglas‐Volkov, Daphna; Ries-Levavi, Liat; Sarouk, Ifat; Pras, Elon; Friedman, Eitan

doi:10.1016/j.cancergen.2015.12.006

Cited by 30 publications

(22 citation statements)

References 29 publications

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“…A second somewhat smaller study found no appreciable increase of blm Ash in colorectal cancer compared to controls, although they did report a nonsignificant increase frequency of blm Ash in adenomas [Cleary et al, 2003]. Other reports have been similarly inconclusive [Zauber et al, 2005;Baris et al, 2007;Laitman et al, 2016]. The Slavic BLM founder mutation (Gln548*) was more common in persons with a first-degree family history of breast cancer [Sokolenko et al, 2012], and the same mutation was associated with an increased risk of breast cancer in a case control study [Prokofyeva et al, 2013].…”

Section: Structure and Function Of The Blm Genementioning

confidence: 86%

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

2016

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Bloom's syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, and a greatly increased risk of early onset of cancer and for the development of multiple cancers. Loss-of-function mutations of BLM, which codes for a RecQ helicase, cause Bloom's syndrome. The absence of a functional BLM protein causes chromosome instability, excessive homologous recombination, and a greatly increased number of sister chromatid exchanges that are pathognomonic of the syndrome. A common founder mutation designated blm^Ash is present in about 1 in 100 persons of Eastern European Jewish ancestry, and there are additional recurrent founder mutations among other populations. Missense, nonsense, and frameshift mutations as well as multiexonic deletions have all been observed. Bloom's syndrome is a prototypical chromosomal instability syndrome, and the somatic mutations that occur as a result of that instability are responsible for the increased cancer risk. Although there is currently no treatment aimed at the underlying genetic abnormality, persons with Bloom's syndrome benefit from sun protection, aggressive treatment of infections, surveillance for insulin resistance, and early identification of cancer.

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Section: Structure and Function Of The Blm Genementioning

confidence: 86%

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

2016

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“…Overall, our results suggest that WDPM are distinctive lesions with their own set of genomic alterations. Given the number of mutations and the nature of the mutations found, including at least one tumor suppressor gene, TP73, and several genes that may be associated with other types of malignancy (ATM, CDH5, MAGED1) [17][18][19], WDPM clearly appears to be a functionally benign neoplasm and not a reactive process. Further, it is clear that WDPM are genetically quite different from both peritoneal and pleural mesotheliomas.…”

Section: Discussionmentioning

confidence: 99%

Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma

Shrestha

Nabavi

Volik³

et al. 2020

Cancers

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Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked the alterations involving BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1, and SMARCC1 that are frequently found in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on observed mutations, do not appear to be precursors of malignant mesotheliomas.

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“…A metanalysis showed that BLM pathogenic variants were associated with a 2 to 5-fold increase in breast cancer 30 . However a longitudinal study showed that the standardized incidence rates for cancer were not higher than expected and thus heterozygous pathogenic variants carriers are not at increased risk for developing cancer 31 . The p.Gln548Ter variant in BLM gene was previously identified as a Slavic founder mutation 30 .…”

Section: Likely Pathogenic Variants Not Reported To Patients In Our Cmentioning

confidence: 91%

Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels

Chirita-Emandi

Andreescu

Zimbru

et al. 2020

Sci Rep

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The benefit of reporting unsolicited findings in Next Generation Sequencing (NGS) related to cancer genes in children may have implications for family members, nevertheless, could also cause distress. We aimed to retrospectively investigate germline variants in 94 genes implicated in oncogenesis, in patients referred to NGS testing for various rare genetic diseases and reevaluate the utility of reporting different classes of pathogenicity. We used in silico prediction software to classify variants and conducted manual review to examine unsolicited findings frequencies in 145 children with rare diseases, that underwent sequencing -using a 4813 gene panel. The anonymized reanalysis revealed 18250 variants, of which 126 were considered after filtering. Six pathogenic variants (in BRCA1,BMPR1A,FANCA,FANCC,NBN genes) with cancer related phenotype and three unsolicited variants (in BRCA2,PALB2,RAD50 genes) were reported to patients. Additionally, three unsolicited variants in ATR, BLM (in two individuals), and FANCB genes presented potential cancer susceptibility, were not reported to patients. In retrospect, 4.8% (7/145) of individuals in our cohort had unsolicited NGS findings related to cancer. More efforts are needed to create an updatable consensus in reporting variants in cancer predisposing genes, especially for children. Consent process is crucial to inform of both value and risk of additional genetic information.

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The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers

Cited by 30 publications

References 29 publications

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma

Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels

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