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

Published on Jun 4, 2021in Breast Cancer Research and Treatment3.831
· DOI :10.1007/S10549-021-06258-9
Ido Laish1
Estimated H-index: 1
(Sheba Medical Center),
Ido Laish7
Estimated H-index: 7
(TAU: Tel Aviv University)
+ 8 AuthorsYael Goldberg17
Estimated H-index: 17
(Rabin Medical Center)
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.
📖 Papers frequently viewed together
7 Authors (Ofer Lavie, ..., Gad Rennert)
38 Citations
1 Citations
5 Citations
Background Lynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasia associated with germline alterations in DNA mismatch repair genes. The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome. Next-generation sequencing (NGS) enables the simultaneous sequencing of a large number of hereditary cancer genes. Here, we aimed to study whether other ...
1 CitationsSource
#1Melyssa AronsonH-Index: 31
#2Chrystelle Colas (University of Paris)H-Index: 25
Last. Uri Tabori (U of T: University of Toronto)H-Index: 66
view all 14 authors...
Background Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and...
4 CitationsSource
#1Mary B. Daly (Fox Chase Cancer Center)H-Index: 88
#2Tuya Pal (Vandy: Vanderbilt University)H-Index: 8
Last. Lcgc (UCSF: University of California, San Francisco)H-Index: 1
view all 34 authors...
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome ...
83 CitationsSource
Poly (ADP-ribose) polymerase inhibitors (PARPi) are a unique class of antineoplastic agents that function by inducing synthetic lethality. Synthetic lethality occurs when PARPi and either another agent or an underlying genetic alteration together lead to overwhelming DNA damage and ultimately cell death. PARPi first showed promise as a cancer therapy in patients with BRCA1/2 mutations and have become part of standard treatment for breast and ovarian cancer. In prostate cancer, two PARPi, rucapar...
14 CitationsSource
#1Mary B. Daly (Fox Chase Cancer Center)H-Index: 88
#1Mary B. Daly (Fox Chase Cancer Center)H-Index: 46
Last. Susan Darlow (National Comprehensive Cancer Network)H-Index: 22
view all 33 authors...
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel...
139 CitationsSource
#1Steven Sorscher (Wake Forest University)H-Index: 14
#2Katherine Cox Ansley (Wake Forest University)H-Index: 3
Last. Shakti H. Ramkissoon (Wake Forest University)H-Index: 17
view all 4 authors...
Background BRCA germline pathogenic variants represent the most common inherited mechanism predisposing individuals to breast cancer, while germline pathogenic variants in one of the mismatch repair (MMR) genes represent the most common colon cancer-predisposing inherited syndrome, known as the Lynch syndrome (LS). Individuals who harbor pathogenic germline variants for both syndromes are extremely rare. Germline testing is now done routinely for patients with breast cancer and MMR testing is re...
4 CitationsSource
#1Agostina StradellaH-Index: 6
#2Jesús del ValleH-Index: 13
Last. Conxi LázaroH-Index: 66
view all 17 authors...
Importance Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations. Objective To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously test...
5 CitationsSource
#1Talia Golan (TAU: Tel Aviv University)H-Index: 14
#2Pascal HammelH-Index: 86
Last. Hedy L. Kindler (U of C: University of Chicago)H-Index: 78
view all 19 authors...
Abstract Background Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate–ribose) polymerase (PARP) in...
533 CitationsSource
#1Mok Oh (UA: University of Arizona)H-Index: 3
#2Ali McBride (UA: University of Arizona)H-Index: 20
Last. Ivo AbrahamH-Index: 51
view all 8 authors...
Background: Investigations of the associations with colorectal cancer have yielded conflicting results. The aim of our study was to synthesize the research on colorectal cancer risks in BRCA mutation carriers by means of a systematic review and quantitatively by means of meta-analyses overall and in subgroups of BRCA mutation carriers. Methods: We searched PubMed/MEDLINE, Embase, Cochrane, Scopus, and ProQuest Dissertation & Theses. Unadjusted odds ratios (ORs) were used to derive pooled estimat...
44 CitationsSource
#1Kathleen N. Moore (OU: University of Oklahoma)H-Index: 44
#2Nicoletta ColomboH-Index: 78
Last. Paul DiSilvestroH-Index: 29
view all 21 authors...
Abstract Background Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the o...
765 CitationsSource
Cited By0