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Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications

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Abstract

Background

Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes.

Methods

Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed.

Results

Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1–2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36–76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines.

Conclusions

This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.

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Data availability

All data generated or analyzed during this study were included in this published article.

Abbreviations

AJ:

Ashkenazi Jewish

CRC:

Colorectal cancer

EC:

Endometrial cancer

GIST:

Gastrointestinal stromal tumor

LOH:

Loss of heterozygosity

HBOC:

Hereditary breast and ovarian cancer syndrome

LS:

Lynch syndrome

MMR:

Mismatch repair

NCCN:

National Comprehensive Cancer Network

NGS:

Next-generation sequencing

PARP:

Poly-ADP ribose polymerase

PV:

Pathogenic variant

RRSO:

Risk-reducing salpingo-oophorectomy

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Acknowledgements

We thank Mrs Gloria Ganzach for linguistic editing.

Funding

No funding was procured for this work.

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Authors and Affiliations

  1. Gastroenterology Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Ido Laish

  2. Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Eitan Friedman

  3. Genetic Institute, Rambam Health Care Campus, Haifa, Israel

    Gili Levi-Reznick

  4. Recanati Genetic Institute, Rabin Medical Center – Beilinson Hospital, 39 Jabotinski St., 4941492, Petach Tikva, Israel

    Inbal Kedar & Yael Goldberg

  5. Department of Gastroenterology and Hepatology, Hadassah Medical Center, Jerusalem, Israel

    Lior Katz

  6. Gastroenterology Institute, Rabin Medical Center – Beilinson Hospital, Petach Tikva, Israel

    Zohar Levi

  7. Department of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Naama Halpern

  8. Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Shani Parnasa

  9. Department of Internal Medicine, Carmel Medical Center, Haifa, Israel

    Aasem Abu-Shatya

  10. Gastroenterology Institute, Rambam Health Care Campus, Haifa, Israel

    Elizabeth Half

  11. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ido Laish, Eitan Friedman, Zohar Levi, Naama Halpern & Yael Goldberg

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  1. Ido Laish
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Correspondence to Yael Goldberg.

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Laish, I., Friedman, E., Levi-Reznick, G. et al. Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications. Breast Cancer Res Treat 188, 685–694 (2021). https://doi.org/10.1007/s10549-021-06258-9

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