Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis

Brazil is the largest country in South America and the most genetically heterogeneous. The aim of the present study was to determine the prevalence of germline pathogenic variants (PVs) in Brazilian patients with breast cancer (BC) who underwent genetic counseling and genetic testing at a tertiary Oncology Center. We performed a retrospective analysis of the medical records of Brazilian patients with BC referred to genetic counseling and genetic testing between August 2017 and August 2019. A total of 224 unrelated patients were included in this study. Premenopausal women represented 68.7% of the cohort. The median age at BC diagnosis was 45 years. Multigene panel testing was performed in 219 patients, five patients performed single gene analysis or family variant testing. Forty-eight germline PVs distributed among 13 genes were detected in 20.5% of the patients (46/224). Eighty-five percent of the patients (91/224) fulfilled NCCN hereditary BC testing criteria. Among these patients, 23.5% harbored PVs (45/191). In the group of patients that did not meet NCCN criteria, PV detection rate was 3% (1/33). A total of 61% of the patients (28/46) harbored a PV in a high-penetrance BC gene: 19 (8.5%) BRCA1/2, 8 (3.5%) TP53, 1 (0.5%) PALB2. Moderate penetrance genes (ATM, CHEK2) represented 15.2% (7/46) of the positive results. PVs detection was statistically associated (p<0.05) with BC diagnosis before age 45, high-grade tumors, bilateral BC, history of multiple primary cancers, and family history of pancreatic cancer. According to the current hereditary cancer guidelines, 17.4% (39/224) of the patients had actionable variants. Nine percent of the patients (20/224) had actionable variants in non-BRCA genes, it represented 43.5% of the positive results and 51.2% of the actionable variants. Considering the observed prevalence of PVs in actionable genes beyond BRCA1/2 (9%, 20/224), multigene panel testing may offer an effective first-tier diagnostic approach in this population.

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Abstract P4-10-13: Analyses of racial disparities in genetic testing and surgical management of patients with triple-negative breast cancer in the era of multigene panel testing

10.1158/1538-7445.sabcs17-p4-10-13 ◽

2018 ◽

Author(s):

D Gopalakrishnan ◽

C Yanda ◽

H Abbas ◽

M Kline ◽

M Stephens ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Racial Disparities ◽

Surgical Management ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Implication and Influence of Multigene Panel Testing with Genetic Counseling in Korean Patients with BRCA1/2 Mutation-Negative Breast Cancer

Cancer Research and Treatment ◽

10.4143/crt.2021.978 ◽

2021 ◽

Author(s):

Ji Soo Park ◽

Saeam Shin ◽

Yoon Jung Lee ◽

Seung-Tae Lee ◽

Eun Ji Nam ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Counseling ◽

Korean Patients ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Multigene Panel Testing Provides a New Perspective on Lynch Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.9260 ◽

2017 ◽

Vol 35 (22) ◽

pp. 2568-2575 ◽

Cited By ~ 68

Author(s):

Carin R. Espenschied ◽

Holly LaDuca ◽

Shuwei Li ◽

Rachel McFarland ◽

Chia-Ling Gau ◽

...

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Lynch Syndrome ◽

Population Based ◽

Brca1 And Brca2 ◽

Panel Testing ◽

Multigene Panel Testing ◽

New Perspective ◽

Testing Criteria ◽

Multigene Panel

Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10−5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10−7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.

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Multigene Panel Testing of Patients With Uterine Carcinoma Reveals Actionable Variants in Non-Canonical Genes [25O]

Obstetrics and Gynecology ◽

10.1097/01.aog.0000559483.56419.f7 ◽

2019 ◽

Vol 133 (1) ◽

pp. 168-169

Author(s):

Dwight Dae-Hoon Im ◽

Arielle Yorczyk ◽

Shan Yang ◽

Scott Michalski ◽

Robert Nussbaum ◽

...

Keyword(s):

Panel Testing ◽

Multigene Panel Testing ◽

Actionable Variants ◽

Multigene Panel

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‘We don’t know for sure’: discussion of uncertainty concerning multigene panel testing during initial cancer genetic consultations

Familial Cancer ◽

10.1007/s10689-019-00154-4 ◽

2019 ◽

Vol 19 (1) ◽

pp. 65-76 ◽

Cited By ~ 2

Author(s):

Niki M. Medendorp ◽

Marij A. Hillen ◽

Pomme E. A. van Maarschalkerweerd ◽

Cora M. Aalfs ◽

Margreet G. E. M. Ausems ◽

...

Keyword(s):

Genetic Counseling ◽

Physician Assistants ◽

Simulated Patient ◽

Cancer Genetic Counseling ◽

Simulated Patients ◽

Cancer Genetic ◽

Multiple Cancer ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

AbstractPre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling. We therefore investigated whether and how counselors discuss and address uncertainty, and the extent of shared decision-making (SDM), and explored associations between counselors’ communication and their characteristics in consultations on panel testing for cancer. For this purpose, consultations of counselors discussing a multigene panel with a simulated patient were videotaped. Simulated patients represented a counselee who had had multiple cancer types, according to a script. Before and afterwards, counselors completed a survey. Counselors’ uncertainty expressions, initiating and the framing of expressions, and their verbal responses to scripted uncertainties of the simulated patient were coded by two researchers independently. Coding was done according to a pre-developed coding scheme using The Observer XT software for observational analysis. Additionally, the degree of SDM was assessed by two observers. Correlation and regression analyses were performed to assess associations of communicated uncertainties, responses and the extent of SDM, with counselors’ background characteristics. In total, twenty-nine counselors, including clinical geneticists, genetic counselors, physician assistants-in-training, residents and interns, participated of whom working experience varied between 0 and 25 years. Counselors expressed uncertainties mainly regarding scientific topics (94%) and on their own initiative (95%). Most expressions were framed directly (77%), e.g. We don’t know, and were emotionally neutral (59%; without a positive/negative value). Counselors mainly responded to uncertainties of the simulated patient by explicitly referring to the uncertainty (69%), without providing space for further disclosure (66%). More experienced counselors provided less space to further disclose uncertainty (p < 0.02), and clinical geneticists scored lower on SDM compared with other types of counselors (p < 0.03). Our findings that counselors mainly communicate scientific uncertainties and use space-reducing responses imply that the way counselors address counselees’ personal uncertainties and concerns during initial cancer genetic counseling is suboptimal.

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Abstract 1236: Insight into genetic susceptibility toBRCA-negative male breast cancer by multigene panel testing: Results from a multicenter study in Italy

10.1158/1538-7445.am2018-1236 ◽

2018 ◽

Cited By ~ 1

Author(s):

Piera Rizzolo ◽

Veronica Zelli ◽

Valentina Silvestri ◽

Virginia Valentini ◽

Alessandro Spinelli ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Susceptibility ◽

Male Breast Cancer ◽

Multicenter Study ◽

Male Breast ◽

Panel Testing ◽

Multigene Panel Testing ◽

Insight Into ◽

Multigene Panel

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Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer

Genetics in Medicine ◽

10.1038/s41436-020-0753-1 ◽

2020 ◽

Vol 22 (5) ◽

pp. 840-846 ◽

Cited By ~ 3

Author(s):

Dana Farengo Clark ◽

Scott T. Michalski ◽

Rashmi Tondon ◽

Bita Nehoray ◽

Jessica Ebrahimzadeh ◽

...

Keyword(s):

Breast Cancer ◽

Loss Of Function ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition

Cancers ◽

10.3390/cancers11091340 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1340 ◽

Cited By ~ 3

Author(s):

Gianluca Tedaldi ◽

Francesca Pirini ◽

Michela Tebaldi ◽

Valentina Zampiga ◽

Ilaria Cangini ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Susceptibility Genes ◽

Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Cancer Susceptibility Genes ◽

Number Of Patients ◽

Multigene Panel Testing ◽

Multigene Panel

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10–50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.

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