Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing

Scarpitta, Rosa; Zanna, Ines; Aretini, Paolo; Gambino, Gaetana; Scatena, Cristian; Mei, Baigen; Ghilli, Matteo; Rossetti, Elena; Roncella, Manuela; Congregati, Caterina; Bonci, Francesca; Naccarato, Antonio Giuseppe; Palli, Domenico; Caligo, Maria A.

doi:10.1007/s10549-019-05429-z

Cited by 26 publications

(27 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likewise, an increased risk of OC in patients with BRCA1/2 DH compared to BRCA2 mutation carriers was found [8]. Furthermore, MBC was present in families with DM, whereas no cases were diagnosed in DH families, thus confirming that BRCA2 mutations have a greater penetrance BC development in men [56]. Similarly, PAC was reported in families with DM but not with DH, further supporting the notion that BRCA2 mutations are associated with an increased risk of PAC [57].…”

Section: Discussionmentioning

confidence: 58%

Five Italian Families with Two Mutations in BRCA Genes

Vietri

Caliendo

Goletti

et al. 2020

Genes

View full text Add to dashboard Cite

Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T>A (IVS8+2T>A)/BRCA2 c.2830A>T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in BRCA2, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of BRCA1 pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.

show abstract

Section: Discussionmentioning

confidence: 58%

Five Italian Families with Two Mutations in BRCA Genes

Vietri

Caliendo

Goletti

et al. 2020

Genes

View full text Add to dashboard Cite

show abstract

“…Then, only limited genetic screening was performed for highly recurrent P/ LPVs in BRCA1 and BRCA2 detected in Slovenian HBOC families [11] and extended genetic analysis was limited only to those with a substantial family history of breast and/or ovarian cancer [9]. Recently published detection rates of P/LPVs in BRCA1 and/or BRCA2 in unselected MBC patients range between 7.8% and 22% in smaller cohorts [28][29][30][31][32]. In two of the largest recently published cohorts, consisting of 382 MBC patients in the collaborative Italian Multicenter Study and 708 mixed population MBC patients tested by Ambry Genetics, California, reported detection rates were 13% and 9%, respectively [33,34].…”

Section: Discussionmentioning

confidence: 99%

Genetic testing results in Slovenian male breast cancer cohort indicate the BRCA2 7806-2A > G founder variant could be associated with higher male breast cancer risk

Strojnik

Krajc

Dragoš

et al. 2021

Breast Cancer Res Treat

View full text Add to dashboard Cite

Purpose To analyze the prevalence of pathogenic/likely pathogenic variants (P/LPVs) in BRCA1 and BRCA2 genes in the largest cohort of Slovenian male breast cancer (MBC) patients to date and to explore a possible correlation between the Slovenian founder variant BRCA2:c.7806-2A > G and predisposition to MBC. Methods We performed a retrospective analysis of 81 MBC cases who underwent genetic counseling and/or testing between January 1999 and May 2020. To explore a possible genotype–phenotype correlation, we performed additional analyses of 203 unrelated families with P/LPVs in BRCA2 and 177 cases of female breast cancer (FBC) in carriers of P/LPVs in BRCA2. Results Detection rate of P/LPVs in the BRCA1 and BRCA2 genes was 24.7% (20/81) with 95% of them in BRCA2 gene. The only two recurrent P/LPVs were BRCA2:c.7806-2A > G and BRCA2:c.3975_3978dupTGCT (9 and 5 MBC cases, respectively). In families with BRCA2:c.7806-2A > G, the incidence of MBC cases was higher compared to families with other P/LPVs in BRCA2; however, the difference did not reach statistical significance (17.8% vs. 8.9%, p = 0.105). BRCA2:c.7806-2A > G was detected in both families with multiple cases of MBC. This splice-site variant represented a significantly higher proportion of all BRCA2 P/LPVs detected in MBC carriers compared to FBC carriers (47.4% vs. 26%, p = 0.049). Conclusion We observed a high mutation detection rate and conclude this may be due to the prevalent BRCA2:c.7806-2A > G variant in Slovenia. Our results indicate a possible association between this variant and higher risk of breast cancer in males compared to other identified P/LPVs in BRCA2.

show abstract

“…Their results are summarized in Table 1. Out of 12314 patients included in 15 studies providing detailed descriptions of the NBN variants detected, 31 (0.25%) carried NBN variants classified or predicted as probably pathogenic/pathogenic (C4/C5) [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. This is consistent with Kurian et al [23] who report a rate of 0.35% (95% CI 0.21-0.55) for pathogenic NBN variants among 5436 patients, whereas NBN VUS were detected in 2.8% (95% CI 2.4-3.3).…”

Section: Review Of the Literaturementioning

confidence: 99%

Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?

Zuntini

Bonora

Pradella

et al. 2021

IJMS

View full text Add to dashboard Cite

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.

show abstract

Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing

Cited by 26 publications

References 46 publications

Five Italian Families with Two Mutations in BRCA Genes

Five Italian Families with Two Mutations in BRCA Genes

Genetic testing results in Slovenian male breast cancer cohort indicate the BRCA2 7806-2A > G founder variant could be associated with higher male breast cancer risk

Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?

Contact Info

Product

Resources

About