Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer

Łukomska, Alicja; Menkiszak, Janusz; Gronwald, Jacek; Tomiczek-Szwiec, Joanna; Szwiec, Marek; Jasiówka, Marek; Blecharz, Paweł; Kluz, Tomasz; Stawicka-Niełacna, Małgorzata; Mądry, Radosław; Białkowska, Katarzyna; Prajzendanc, Karolina; Kluźniak, Wojciech; Cybulski, Cezary; Dębniak, Tadeusz; Huzarski, Tomasz; Tołoczko‐Grabarek, Aleksandra; Byrski, Tomasz; Baszuk, Piotr; Narod, Steven A.; Lubiński, Jan; Jakubowska, Anna

doi:10.3390/cancers13040849

Cited by 16 publications

(21 citation statements)

References 47 publications

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“…A panel of BRCA1 and BRCA2 variants, including close to 100 recurrent variants (HISPANEL), has been constructed with diverse variants from Hispanic women with BC from the USA, based on the information in manuscripts describing variants in BRCA genes from Latin American countries and data bases [71]. In Poland, Łukomska et al, recommend that all women with OC and rstdegree female relatives should be tested for the panel of 18 founder variants in BRCA1, BRCA2, PALB2, and RAD51C [72]. In addition to the known founder deleterious variants in the Chinese population, Jiang et al, highlight that the recurrent PVs in BC patients could be taken as candidate genetic screening loci for a more e cient genetic screening of this population [73].…”

Section: Discussionmentioning

confidence: 99%

Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa

ElBiad¹,

Laraqui²,

Boukhrissi³

et al. 2021

Preprint

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Background Elucidation of specific and recurrent/founder pathogenic variants (PVs) in BRCA (BRCA1 and BRCA2) genes can have an impact on breast cancer (BC) and/or ovarian cancer (OC) risk, making genetic testing affordable and accessible. Methods To establish the knowledge about BRCA PVs and to determine the prevalence of the specific and recurrent/founder variants in BRCA genes in BC and/or OC women in North Africa, a systematic review was conducted in Morocco, Algeria, and Tunisia. Results Search of the databases yielded 25 relevant references, including eleven studies in Morocco, five in Algeria, and nine in Tunisia. Overall, 15 studies investigated both BRCA1 and BRCA2 genes, four studies examined the entire coding region of the BRCA1 gene, and six studies in which the analysis was limited to a few BRCA1 and/or BRCA2 exons. Overall, 76 PVs (44 in BRCA1 and 32 in BRCA2) were identified in 196 BC and/or OC patients (129 BRCA1 and 67 BRCA2 carriers). Eighteen of the 76 (23.7%) PVs [10/44 (22.7%) in BRCA1 and 8/32 (25%) in BRCA2] were reported for the first time and considered to be novel PVs. Among those identified as unlikely to be of North African origin, the BRCA1 c.68_69del and BRCA1 c.5266dupC Jewish founder alleles and PVs that have been reported as recurrent/founder variants in European populations (ex: BRCA1 c.181T > G, BRCA1 c1016dupA). The most well characterized PVs are four in BRCA1 gene [c.211dupA (14.7%), c.798_799detTT (14%), c.5266dup (8.5%), c.5309G > T (7.8%), c.3279delC (4.7%)] and one in BRCA2 [c.1310_1313detAAGA (38.9%)]. The c.211dupA and c.5309G > T PVs were identified as specific founder variants in Tunisia and Morocco, accounting for 35.2% (19/54) and 20.4% (10/49) of total established BRCA1 PVs, respectively. c.798_799delTT variant was identified in 14% (18/129) of all BRCA1 North African carriers, suggesting a founder allele. A broad spectrum of recurrent variants including BRCA1 3279delC, BRCA1 c.5266dup and BRCA2 c.1310_1313detAAGA was detected in 42 patients. BRCA1 founder variants explain around 36.4% (47/129) of BC and outnumber BRCA2 founder variants by a ratio of ≈ 3:1. Conclusion Testing BC and/or OC patients for the panel of specific and recurrent/founder PVs might be the most cost-effective molecular diagnosis strategy.

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Section: Discussionmentioning

confidence: 99%

Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa

ElBiad¹,

Laraqui²,

Boukhrissi³

et al. 2021

Preprint

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“…Based on reported pathological and molecular similarities of BOTs and low-grade invasive ovarian tumors [ 23 , 24 ], 167 women with low-grade ovarian cancer (grade 1—G1) were additionally included in analyses. The patients with ovarian cancer G1 were selected from a group of 2270 consecutive ovarian cancer cases described earlier [ 5 ]. The obtained clinical information included age at diagnosis, tumor histology, and family history of ovarian cancers.…”

Section: Methodsmentioning

confidence: 99%

“…Although the prognosis in BOT patients is generally excellent, serous borderline tumors can implant on peritoneal surfaces and progress to low-grade serous ovarian carcinoma [ 2 , 3 ]. There are several genes associated with the risk of ovarian cancer [ 5 – 9 ]; however, very little is known about germline mutations related to BOTs [ 10 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor

Ogrodniczak

Menkiszak

Gronwald

et al. 2022

Hered Cancer Clin Pract

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Background There are several genes associated with ovarian cancer risk. Molecular changes in borderline ovarian tumor (BOT) indicate linkage of this disease to type I ovarian tumors (low-grade ovarian carcinomas). This study determined the prevalence and association of mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 with the risk of BOTs. Methods The study group consisted of 102 patients with histologically confirmed BOT and 1743 healthy controls. In addition, 167 cases with ovarian cancer G1 were analyzed. The analyses included genotyping of 21 founder and recurrent mutations localized in 5 genes (BRCA1, BRCA2, PALB2, RAD51C, and CHEK2). The risk for developing BOT and low-grade ovarian cancer, as well as the association of tested mutations with survival, was estimated. Results The CHEK2 missense mutation (c.470T>C) was associated with 2-times increased risk of BOT (OR=2.05, p=0.03), at an earlier age at diagnosis and about 10% worse rate of a 10-year survival. Mutations in BRCA1 and PALB2 were associated with a high risk of ovarian cancer G1 (OR=8.53, p=0.005 and OR=7.03, p=0.03, respectively) and were related to worse all-cause survival for BRCA1 carriers (HR=4.73, 95%CI 1.45–15.43, p=0.01). Conclusions Results suggest that CHEK2 (c.470T>C) may possibly play a role in the pathogenesis of BOT, but due to the low number of BOT patients, obtained results should be considered as preliminary. Larger more in-depth studies are required.

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“…BRCA1 c.1016dupA has been reported in the literature as a founder variant in Norway and Canada (13,14) and also in multiple individuals affected with hereditary breast and ovarian cancer syndrome in other populations (15)(16)(17)(18). Case 2 four-nucleotide deletion was widely reported in the literature in Polish and French-Canadian gynecological cancer patients (19,20). The BRCA1 variant present in case 3 has been reported as a France, Belgium, and Holland founder variant (21).…”

Section: Case Descriptionmentioning

confidence: 97%

Case Report Series: Aggressive HR Deficient Colorectal Cancers Related to BRCA1 Pathogenic Germline Variants

et al. 2022

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ObjectiveThe link between BRCA1 and homologous recombination deficiency (HRD) in cancer has gained importance with the emergence of new targeted cancer treatments, while the available data on the role of the gene in colorectal cancer (CRC) remain contradictory. The aim of this case series was to elucidate the role of known pathogenic BRCA1 variants in the development of early-onset CRC.DesignPatients were evaluated using targeted next generation sequencing, exome sequencing and chromosomal microarray analysis of the paired germline and tumor samples. These results were used to calculate the HRD score and the frequency of mutational signatures in the tumors.ResultsThree patients with metastatic CRC were heterozygous for a previously known BRCA1 nonsense variant. All tumors showed remarkably high HRD scores, and the HRD-related signature 3 had the second highest contribution to the somatic pattern of variant accumulation in the samples (23% in 1 and 2, and 13% in sample 3).ConclusionsA BRCA1 germline pathogenic variant can be involved in CRC development through HRD. Thus, BRCA1 testing should be considered in young patients with a personal history of microsatellite stable CRC as this could further allow a personalized treatment approach.

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Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer

Cited by 16 publications

References 47 publications

Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa

Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa

Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor

Case Report Series: Aggressive HR Deficient Colorectal Cancers Related to BRCA1 Pathogenic Germline Variants

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