First evidence of a large CHEK2 duplication involved in cancer predisposition in an Italian family with hereditary breast cancer

Tedaldi, Gianluca; Danesi, Rita; Zampiga, Valentina; Tebaldi, Michela; Bedei, Lucia; Zoli, Wainer; Amadori, Dino; Falcini, Fabio; Calistri, Daniele

doi:10.1186/1471-2407-14-478

Cited by 13 publications

(18 citation statements)

References 21 publications

(28 reference statements)

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“…A family history of breast cancer is considered a significant risk factor to develop the disease and it is thought that 15 % of women diagnosed with breast cancer have at least one first degree relative with breast cancer. Germline mutations in BRCA1 and BRCA2 have been associated with approximately 25 % of hereditary breast cancers and 13-15 % of ovarian cancers in patients with a family history of breast or ovarian cancer (Kean 2014;Tedaldi et al 2014;Walsh et al 2011). Therefore, a large portion of this patient population with breast and/or ovarian cancer has another cause of hereditary cancer, likely due to a mutation in other susceptibility genes.…”

Section: Introductionmentioning

confidence: 99%

The Clinical Utility of Next Generation Sequencing Results in a Community‐Based Hereditary Cancer Risk Program

Bunnell

Garby

Pearson

et al. 2016

Journal of Genetic Counseling

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Since the 2013 Supreme Court ruling on BRCA1/BRCA2 patenting, hereditary cancer gene panels now include BRCA1 and BRCA2, making these panels an option for first-tier testing. However, questions remain about the clinical utility and implications of these panels for medical management with inclusion of genes of unknown to moderate penetrance. To better understand how use of these panels affected our practice, we reviewed patients who underwent testing in our clinic from July 1, 2013 through May 23, 2014. Indications for testing included personal and/or family history of breast and/or ovarian cancer. A total of 136 patients underwent panel testing via a single commercial laboratory; 12 (8.8 %) patients were positive for a pathogenic or likely pathogenic mutation (four BRCA2 mutations, two TP53 mutations, one CDH1 mutation, two ATM mutations, and one patient each with a CHEK2, NBN, or PALB2 mutation). Of these positive patients, 100 % met the National Comprehensive Cancer Network (NCCN) guidelines for Hereditary Breast and Ovarian Cancer genetic testing (2.2014). Mutations in seven of twelve (58 %) patients led to changes in medical management; three of seven (43 %) had a non-BRCA1 or BRCA2 gene mutation. Our findings suggest that there is clinical utility of panels that include genes of unknown to moderate penetrance.

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Section: Introductionmentioning

confidence: 99%

The Clinical Utility of Next Generation Sequencing Results in a Community‐Based Hereditary Cancer Risk Program

Bunnell

Garby

Pearson

et al. 2016

Journal of Genetic Counseling

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“…The first CHEK2 germline PV/LPVs identified have been associated with the Li-Fraumeni syndrome [152,153]; subsequently, this association has been questioned because of phenotype differences among LFS patients and CHEK2 PV/LPV carriers [154]. Germline PV/LPVs in this gene are associated with an increased risk of BC [155][156][157][158], which is estimated to be 25-39% during a lifetime [29,159,160]. In particular, CHEK2 variant c.1100delC is associated with a two-to three-fold increase in BC risk in women and a ten-fold increase of risk in men [161][162][163].…”

Section: Chek2mentioning

confidence: 99%

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

Angeli

Salvi

Tedaldi

2020

IJMS

Self Cite

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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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“…breast cancer and prostate cancer [43,44]. Several different CHEK2 mutations have been described [40,42], 5 of which have been associated with increased breast cancer risks. These CHEK2 variants appear to confer moderate breast cancer risks (2-4-fold) and seem to vary widely among different geographical and ethnic populations [45].…”

Section: Pathological Characteristics Of Hereditary Breast Cancersmentioning

confidence: 99%

“…The CHEK2 gene (coding for checkpoint kinase 2) is a tumor suppressor gene located on the long arm of chromosome 22 (22q12.1) [40]. It encodes a nuclear protein which, in response to DNA damage (i.e.…”

Section: Pathological Characteristics Of Hereditary Breast Cancersmentioning

confidence: 99%

“…It encodes a nuclear protein which, in response to DNA damage (i.e. double-strand breaks), is phosphorylated by ATM and subsequently catalyzes the phosphorylation of several substrates, thereby regulating cell cycle progression and protecting cells against too rapid, uncontrolled growth [40,41,42]. …”

Section: Pathological Characteristics Of Hereditary Breast Cancersmentioning

confidence: 99%

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Genotype/Phenotype Correlations in Patients with Hereditary Breast Cancer

2015

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Of all breast cancer cases, 5-10% can be attributed to germline mutations, and the high-susceptibility genes BRCA1 and BRCA2 account for about 25-28% of these cases. For the remainder, several genes of moderate and low penetrance have been discovered. Histopathologic characteristics have been studied in small cohorts, but for most of the known non-BRCA1/2-associated hereditary breast cancers, the histologic and immunohistochemical phenotypes are not yet identified. Particularly BRCA1 tumors are associated with a distinct morphology and immunohistochemical characteristics that differ from sporadic breast cancer of age-matched controls. The recognition of features characteristic of these mutations can be helpful to identify patients likely to carry a germline mutation and to assess which gene should be screened for first, in families with a high occurrence of breast and ovarian cancer.

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First evidence of a large CHEK2 duplication involved in cancer predisposition in an Italian family with hereditary breast cancer

Cited by 13 publications

References 21 publications

The Clinical Utility of Next Generation Sequencing Results in a Community‐Based Hereditary Cancer Risk Program

The Clinical Utility of Next Generation Sequencing Results in a Community‐Based Hereditary Cancer Risk Program

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

Genotype/Phenotype Correlations in Patients with Hereditary Breast Cancer

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