Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations

Sokolenko, Anna P.; Bogdanova, Natalia; Kluźniak, Wojciech; Preobrazhenskaya, Elena V.; Kuligina, Ekatherina Sh.; Iyevleva, Aglaya G.; Aleksakhina, Svetlana N.; Mitiushkina, Natalia V.; Gorodnova, Tatiana V.; Bessonov, Alexandr A.; Togo, Alexandr V.; Lubiński, Jan; Cybulski, Cezary; Jakubowska, Anna; Dörk, Thilo; Imyanitov, Evgeny N.

doi:10.1007/s10549-014-2971-1

Cited by 51 publications

(41 citation statements)

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“…This is a common BRCA1 mutation in ovarian cancer patients from Belarus [3], so the co-inheritance may be a chance finding. But the observation is in line with results from breast cancer studies that BLM truncations can coincide with BRCA1 mutations [7,9,15,17]. The BLM mutation was further investigated for LOH in one serous ovarian (Table 3).…”

Section: Methodssupporting

confidence: 80%

Prevalence of the BLM nonsense mutation, p.Q548X, in ovarian cancer patients from Central and Eastern Europe

et al. 2014

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A nonsense mutation, p.Q548X, in the BLM gene has recently been associated with an increased risk for breast cancer. In the present work, we investigated the prevalence of this Slavic founder mutation in 2,561 ovarian cancer cases from Russia, Belarus, Poland, Lithuania or Germany and compared its frequency with 6,205 ethnically matched healthy female controls. The p.Q548X allele was present in nine ovarian cancer patients of Slavic ancestry (0.5 %; including one case with concurrent BRCA1 mutation). The mutation was not significantly more frequent in cases than in controls (Mantel-Haenszel OR 1.14, 95 % CI 0.49; 2.67). Ovarian tumours in p.Q548X carriers were mainly of the serous subtype, and there was little evidence for an early age at diagnosis or pronounced family history of cancer. These findings indicate that the BLM p.Q548X mutation is not a strong risk factor for ovarian cancer.

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Section: Methodssupporting

confidence: 80%

Prevalence of the BLM nonsense mutation, p.Q548X, in ovarian cancer patients from Central and Eastern Europe

et al. 2014

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“…Similarly, many reported findings on candidate breast-cancer predisposing genes were subsequently validated in independent studies and turned out to be relevant to significant share of breast cancer patients. For example, CHEK2 mutations contribute to 2-3% of BC incidence at least in some European countries and are associated with moderate but nevertheless clinically meaningful elevation of risk of the disease [7,122,123]. The role of PALB2 was also revealed via candidate gene approach, and convincingly replicated in other patient series [124][125][126].…”

Section: Breast Cancermentioning

confidence: 90%

“…Ashkenazi Jews and Icelanders represent the most known founder populations [153]. Somewhat surprisingly, Eastern Slavs residing in Russia, Poland, Ukraine and Belarus are also characterized by pronounced founder effect, and apparently represent the largest known founder community in the world [123].…”

Section: Article In Pressmentioning

confidence: 99%

“…However, genomewide association studies (GWAS) are unable to discover rare diseasepredisposing variants. Some data sets demonstrate that the frequency of double heterozygosity for known predisposing genes (BRCA1, CHEK2, NBS, BLM, ATM) is higher in breast cancer patients than expected by chance [123]. Therefore, rare germ-line defects may act in a cooperative manner for cancer development.…”

Section: Article In Pressmentioning

confidence: 99%

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Identification of novel hereditary cancer genes by whole exome sequencing

et al. 2015

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Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years.

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“…Petrov Institute of Oncology (St.-Petersburg) within years [10][11][12][13]. In addition, we considered previously obtained results of the analysis of entire BRCA1-coding region [14].…”

Section: Methodsmentioning

confidence: 99%

Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers

Pfeifer

Sokolenko

Potapova

et al. 2014

Breast Cancer Res Treat

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Breast carcinomas caused by inheritance of cancer-predisposing germ-line mutations have specific bioclinical features. This study aimed to analyze the efficacy of conventional cytotoxic treatment in BRCA1 and CHEK2 mutation carriers and non-carriers. The study included 415 Russian breast cancer patients aged 50 years or younger, who were subjected to various standard schemes of neoadjuvant therapy. The choice of therapy was done without the knowledge of the mutations status, because DNA testing was performed retrospectively using the archival tissue samples. 19 BRCA1 (4.6%) and 8 CHEK2 (1.9%) heterozygous genotypes were identified. BRCA1 mutation carriers achieved pathological complete response more frequently than non-carriers [6/19 (31.6%) vs. 46/388 (11.9%), p = 0.024]; this effect was limited to women treated by anthracycline-based therapy without taxanes [5/9 (55.6%) vs. 28/247 (11.3%), p = 0.002] and was not observed in any of 7 BRCA1 carriers receiving taxane-containing regimens. CHEK2 heterozygotes did not experience pathological complete response and showed lower frequency of objective clinical responses as compared to mutation non-carriers [4/8 (50%) vs. 333/388 (85.5%), p = 0.020]; the efficacy of neoadjuvant therapy was particularly poor in CHEK2 carriers receiving anthracyclines without taxanes. This study provides evidence for distinct sensitivity of BRCA1 and CHEK2 mutation-driven breast carcinomas to standard chemotherapeutic schemes.

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Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations

Cited by 51 publications

References 40 publications

Prevalence of the BLM nonsense mutation, p.Q548X, in ovarian cancer patients from Central and Eastern Europe

Prevalence of the BLM nonsense mutation, p.Q548X, in ovarian cancer patients from Central and Eastern Europe

Identification of novel hereditary cancer genes by whole exome sequencing

Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers

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