Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Rizzolo, Piera; Zelli, Veronica; Silvestri, Valentina; Valentini, Virginia; Zanna, Ines; Bianchi, Simonetta; Masala, Giovanna; Spinelli, Alessandro Mauro; Tibiletti, Maria Grazia; Russo, Antonio; Varesco, Liliana; Giannini, Giuseppe; Capalbo, Carlo; Calistri, Daniele; Cortesi, Laura; Viel, Alessandra; Bonanni, Bernardo; Azzollini, Jacopo; Manoukian, Siranoush; Montagna, Marco; Peterlongo, Paolo; Radice, Paolo; Palli, Domenico; Ottini, Laura

doi:10.1002/ijc.32106

Cited by 41 publications

(63 citation statements)

References 47 publications

(77 reference statements)

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“…8,9,[33][34][35][36] The current analysis confirms the association with PaC and is the first in our knowledge to quantify it, with an RR estimate of 2.30 (albeit with wide confidence limits), which translates to an absolute risk of 2%-3% by age 80 years (Fig 2; Table 2). Previous studies observed a higher prevalence of PALB2 PVs in MBC, 5,[37][38][39] No previous study that we know of has demonstrated statistically significant associations of PALB2 with PrC risk, 25,[40][41][42] and our analysis points to a weak association with decreased risk. Because families were primarily ascertained through female individuals with BC and OC, this result might reflect under-reporting of PrC in these families, and the same phenomenon could explain the slightly decreased risk for all other cancers.…”

Section: Discussioncontrasting

confidence: 54%

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Yang

Leslie

Doroszuk

et al. 2020

JCO

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PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

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Section: Discussioncontrasting

confidence: 54%

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Yang

Leslie

Doroszuk

et al. 2020

JCO

Self Cite

284

245

View full text Add to dashboard Cite

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“…Over the last few years, thanks to the extensive use of NGS technology, several genes other than BRCA1/2, have been associated with increased BC/OC risk. To date, a wide range of NGS panels are available for the analysis of hereditary BC/OC [86]; generally, these panels include high-penetrance BC/OC genes (BRCA1 and BRCA2), moderate/low-penetrance genes (e.g., PALB2, CHEK2 and ATM), mismatch repair genes (e.g., MLH1 and MSH2), and genes related to hereditary cancer syndromes (e.g., CDH1, PTEN, STK11 and TP53) [87]. Overall, a critical factor for NGS panel use is that a high number of variants of unknown significance (VUS) are detected, for which clinical management is unclear.…”

Section: Pros and Cons Of Ngs Approaches For The Analysis Of Familialmentioning

confidence: 99%

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

et al. 2020

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Next generation sequencing (NGS) provides a powerful tool in the field of medical genetics, allowing one to perform multi-gene analysis and to sequence entire exomes (WES), transcriptomes or genomes (WGS). The generated high-throughput data are particularly suitable for enhancing the understanding of the genetic bases of complex, multi-gene diseases, such as cancer. Among the various types of tumors, those with a familial predisposition are of great interest for the isolation of novel genes or gene variants, detectable at the germline level and involved in cancer pathogenesis. The identification of novel genetic factors would have great translational value, helping clinicians in defining risk and prevention strategies. In this regard, it is known that the majority of breast/ovarian cases with familial predisposition, lacking variants in the highly penetrant BRCA1 and BRCA2 genes (non-BRCA), remains unexplained, although several less penetrant genes (e.g., ATM, PALB2) have been identified. In this scenario, NGS technologies offer a powerful tool for the discovery of novel factors involved in familial breast/ovarian cancer. In this review, we summarize and discuss the state of the art applications of NGS gene panels, WES and WGS in the context of familial breast/ovarian cancer.

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“…Breast cancer (BC) and ovarian cancer (OC) are the first and the eighth most common tumors for both incidence and mortality in females, respectively [1]. BC can also affect males, even if male breast cancer (MBC) represents less than 1% of all BCs [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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

Angeli

Salvi

Tedaldi

2020

IJMS

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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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Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Cited by 41 publications

References 47 publications

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

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

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