Evidence for an ancient BRCA1 pathogenic variant in inherited breast cancer patients from Senegal

Abstract Background Diagnostic screening for pathogenic variants in breast cancer susceptibility genes, including BRCA1, BRCA2, PALB2, PTEN and TP53, may be offered to New Zealanders from suspected high-risk breast (and ovarian) cancer families. However, it is unknown how many high-risk pathogenic variant carriers in New Zealand are not offered genetic screening using existing triage tools and guidelines for breast (and ovarian) cancer patients. Methods Panel-gene sequencing of the coding and non-coding regions of the BRCA1 and BRCA2 genes, and the coding regions and splice sites of CDH1, PALB2, PTEN and TP53, was undertaken for an unselected cohort of 367 female breast cancer patients. A total of 1685 variants were evaluated using the ENIGMA and the ACMG/AMP variant classification guidelines. Results Our study identified that 13 (3.5%) breast cancer patients carried a pathogenic or likely pathogenic variant in BRCA1, BRCA2, PALB2, or PTEN. A significantly higher number of pathogenic variant carriers had grade 3 tumours (10/13) when compared to non-carriers; however, no other clinicopathological characteristics were found to be significantly different between (likely) pathogenic variant carriers and non-carriers, nor between variant of unknown significance carriers and non-carriers. Notably, 46% of the identified (likely) pathogenic variant carriers had not been referred for a genetic assessment and consideration of genetic testing. Conclusion Our study shows a potential under-ascertainment of women carrying a (likely) pathogenic variant in a high-risk breast cancer susceptibility gene. These results suggest that further research into testing pathways for New Zealand breast cancer patients may be required to reduce the impact of hereditary cancer syndromes for these individuals and their families.

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Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico

Scientific Reports ◽

10.1038/s41598-019-54170-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Julie Dutil ◽

Jamie K. Teer ◽

Volha Golubeva ◽

Sean Yoder ◽

Wei Lue Tong ◽

...

Keyword(s):

Breast Cancer ◽

Puerto Rico ◽

High Risk ◽

Cancer Patients ◽

Significant Proportion ◽

Pathogenic Variant ◽

Breast Cancer Patients ◽

Missense Variants ◽

Pathogenic Variants

AbstractInherited pathogenic variants in genes that confer moderate to high risk of breast cancer may explain up to 50% of familial breast cancer. This study aimed at identifying inherited pathogenic variants in breast cancer cases from Puerto Rico that were not linked to BRCA1 or BRCA2. Forty-eight breast cancer patients that met the clinical criteria for BRCA testing but had received a negative BRCA1/2 result were recruited. Fifty-three genes previously implicated in hereditary cancer predisposition were captured using the BROCA Agilent cancer risk panel followed by massively parallel sequencing. Missense variants of uncertain clinical significance in CHEK2 were evaluated using an in vitro kinase assays to determine their impact on function. Pathogenic variants were identified in CHEK2, MUTYH, and RAD51B in four breast cancer patients, which represented 8.3% of the cohort. We identified three rare missense variants of uncertain significance in CHEK2 and two variants (p.Pro484Leu and p.Glu239Lys) showed markedly decreased kinase activity in vitro comparable to a known pathogenic variant. Interestingly, the local ancestry at the RAD51B locus in the carrier of p.Arg47* was predicted to be of African origin. In this cohort, 12.5% of the BRCA-negative breast cancer patients were found to carry a known pathogenic variant or a variant affecting protein activity. This study reveals an unmet clinical need of genetic testing that could benefit a significant proportion of at-risk Latinas. It also highlights the complexity of Hispanic populations as pathogenic factors may originate from any of the ancestral populations that make up their genetic backgrounds.

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The Angelina Jolie effect: Contralateral risk-reducing mastectomy trends in patients at increased risk of breast cancer

Scientific Reports ◽

10.1038/s41598-021-82654-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Narendra Nath Basu ◽

James Hodson ◽

Shaunak Chatterjee ◽

Ashu Gandhi ◽

Julie Wisely ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Pathogenic Variant ◽

Lifetime Risk ◽

Breast Cancer Patients ◽

Unilateral Breast Cancer ◽

Increased Risk ◽

Angelina Jolie ◽

The Impact ◽

Risk Reducing

AbstractContralateral risk-reducing mastectomy (CRRM) rates have tripled over the last 2 decades. Reasons for this are multi-factorial, with those harbouring a pathogenic variant in the BRCA1/2 gene having the greatest survival benefit. On May 14th, 2013, Angelina Jolie shared the news of her bilateral risk-reducing mastectomy (BRRM), on the basis of her BRCA1 pathogenic variant status. We evaluated the impact of this news on rates of CRRM in women with increased risk for developing breast cancer after being diagnosed with unilateral breast cancer. The prospective cohort study included all women with at least a moderate lifetime risk of developing breast cancer who attended our family history clinic (1987–2019) and were subsequently diagnosed with unilateral breast cancer. Rates of CRRM were then compared between patients diagnosed with breast cancer before and after Angelina Jolie’s announcement (pre- vs. post-AJ). Of 386 breast cancer patients, with a mean age at diagnosis of 48 ± 8 years, 268 (69.4%) were diagnosed in the pre-AJ period, and 118 (30.6%) in the post-AJ period. Of these, 123 (31.9%) underwent CRRM, a median 42 (interquartile range: 11–54) days after the index cancer surgery. Rates of CRRM doubled following AJ’s news, from 23.9% pre-AJ to 50.0% post AJ (p < 0.001). Rates of CRRM were found to decrease with increasing age at breast cancer (p < 0.001) and tumour TNM stage (p = 0.040), and to increase with the estimated lifetime risk of breast cancer (p < 0.001) and tumour grade (p = 0.015) on univariable analysis. After adjusting for these factors, the step-change increase in CRRM rates post-AJ remained significant (odds ratio: 9.61, p < 0.001). The AJ effect appears to have been associated with higher rates of CRRM amongst breast cancer patients with increased cancer risk. CRRM rates were highest amongst younger women and those with the highest lifetime risk profile. Clinicians need to be aware of how media news can impact on the delivery of cancer related services. Communicating objective assessment of risk is important when counselling women on the merits of risk-reducing surgery.

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