St Petersburg Pediatric Medical Academy

Russian Federation, Russia

St Petersburg Pediatric Medical Academy

Russian Federation, Russia
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Mavaddat N.,University of Cambridge | Barrowdale D.,University of Cambridge | Andrulis I.L.,Samuel Lunenfeld Research Institute | Andrulis I.L.,University of Toronto | And 136 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012

Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10-5), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10-6). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10-13 for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10-14), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10-15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. ©2011 AACR.


Russnes H.G.,University of Oslo | Kuligina E.S.,Nn Petrov Institute Of Oncology | Suspitsin E.N.,St Petersburg Pediatric Medical Academy | Voskresenskiy D.A.,St Petersburg Medical Academy For Postgraduate Studies | And 4 more authors.
Cancer Genetics | Year: 2011

The last decade has revealed fundamental new insight into the existence of intrinsic molecular subclasses of breast carcinomas. By using immunostaining on archival tissue, we classified tumor pairs from 50 patients with bilateral disease into molecular subgroups (luminal, triplenegative basal-like, and triple-negative unclassified). Synchronous tumors showed a slightly higher rate of concordant pairs than metachronous tumors, and luminal tumors were highly concordant regardless of being synchronous or metachronous (P Z 0.001 and P Z 0.002, respectively). Metachronous cases had a higher degree of discordance if the time interval was longer than 10 years; this was most pronounced for triple-negative tumors. The relationship found between subtypes of bilateral tumors provides additional evidence for the role of host-related factors in determining the molecular type of breast cancer. © 2011 Elsevier Inc.


Ulybina Y.M.,Nn Petrov Institute Of Oncology | Kuligina E.S.,Nn Petrov Institute Of Oncology | Mitiushkina N.V.,Nn Petrov Institute Of Oncology | Sherina N.Y.,Nn Petrov Institute Of Oncology | And 6 more authors.
Tumori | Year: 2011

Aims and background. Comparison of subjects with extreme phenotypes of cancer susceptibility and tolerance allows to detect low-penetrance gene-disease interactions with a relatively small study size. Methods and study design. We analyzed the distribution of 19 coding apoptotic gene polymorphisms (Bid Gly10Ser; Casp2 Leu141Val; Casp5 Ala90Thr and Val318Leu; Casp7 Glu255Asp; Casp8 His302Asp; Casp9 Val28Ala, His173Arg and Arg221Gln; Casp10 Ile479Leu; Faim Thr117Ala and Ser127Leu; DR4 Arg141His, Thr209Arg, Ala228Glu and Lys441Arg; Survivin Lys129Glu; TNFR1 Gln121Arg; XIAP Pro423Gln) in 121 breast cancer patients with clinical features of a hereditary predisposition (family history and/or early onset and/or bilaterality) and 142 elderly tumor-free women. Results. None of the individual single nucleotide polymorphisms (SNPs) demonstrated an association with breast cancer risk. The analysis of gene interactions revealed that the combination of XIAP Pro423Gln (rs5956583) AA genotype with Casp7 Glu255Asp (rs2227310) CG genotype appeared to prevail in "supercases" relative to "supercontrols" (25/121 [21%] vs 11/142 [8%], P = 0.002). We attempted to validate this association in the second round of case-control analysis, which involved 519 randomly selected breast cancer patients and 509 age-matched healthy women, but no difference was detected upon this comparison. Conclusions. Coding apoptotic gene polymorphisms do not play a major role in BC predisposition. The results of this investigation may be considered while designing future studies on breast cancer-associated candidate SNPs.


Iyevleva A.G.,St Petersburg Pediatric Medical Academy | Suspitsin E.N.,St Petersburg Pediatric Medical Academy | Kroeze K.,Leiden University | Gorodnova T.V.,St Petersburg Pediatric Medical Academy | And 8 more authors.
Cancer Letters | Year: 2010

A few founder BRCA1 mutations (5382insC, 4154delA, 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia. The impact of non-founder BRCA1 mutations in this country is less studied; in particular, there are no reports analyzing gross rearrangements of this gene in the Russian patient series. We selected for the study 95 founder mutation negative high-risk BC cases. Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C > G, 5214C > T, 5236G > A, 5460G > T, 5622C > T) and one variant of an unknown significance (4885G > A). The pathogenic role of the 5236G > A mutation leading to G1706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes, which carried BRCA1 deletions involving exons 1-2 and 3-7, respectively. Based on the results of this investigation and the review of prior Russian studies, three BRCA1 mutations (2080delA, 3819del5, 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients; two BRCA heterozygotes (2080delA and 3819del5) were revealed. We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia. © 2010 Elsevier Ireland Ltd.


Sokolenko A.P.,St Petersburg Pediatric Medical Academy | Iyevleva A.G.,St Petersburg Pediatric Medical Academy | Preobrazhenskaya E.V.,Nn Petrov Institute Of Oncology | Mitiushkina N.V.,Nn Petrov Institute Of Oncology | And 18 more authors.
International Journal of Cancer | Year: 2012

The BLM gene belongs to the RecQ helicase family and has been implicated in the maintenance of genomic stability. Its homozygous germline inactivation causes Bloom syndrome, a severe genetic disorder characterized by growth retardation, impaired fertility and highly elevated cancer risk. We hypothesized that BLM is a candidate gene for breast cancer (BC) predisposition. Sequencing of its entire coding region in 95 genetically enriched Russian BC patients identified two heterozygous carriers of the c.1642 C>T (Q548X) mutation. The extended study revealed this allele in 17/1,498 (1.1%) BC cases vs. 2/1,093 (0.2%) healthy women (p = 0.004). There was a suggestion that BLM mutations were more common in patients reporting first-degree family history of BC (6/251 (2.4%) vs. 11/1,247 (0.9%), p = 0.05), early-onset cases (12/762 (1.6%) vs. 5/736 (0.7%), p = 0.14) and women with bilateral appearance of the disease (2/122 (1.6%) vs. 15/1376 (1.1%), p = 0.64). None of the BLM-associated BC exhibited somatic loss of heterozygosity at the BLM gene locus. This study demonstrates that BLM Q548X allele is recurrent in Slavic subjects and may be associated with BC risk. Copyright © 2011 UICC.


Ulybina Y.M.,Nn Petrov Institute Of Oncology | Kuligina E.S.,Nn Petrov Institute Of Oncology | Mitiushkina N.V.,Nn Petrov Institute Of Oncology | Sherina N.Y.,Nn Petrov Institute Of Oncology | And 6 more authors.
Experimental Gerontology | Year: 2010

Our previous studies, which included genotyping of multiple coding apoptotic gene polymorphisms, unexpectedly demonstrated a depletion of heterozygous CASP5 Ala90Thr (rs507879, c.268 G > A) genotypes in elderly subjects. Present investigation was aimed to validate this trend. An analysis of 510 subjects aged 75-103. years revealed 205 (40%) CASP5 Ala90Thr heterozygotes as compared to 254 (50%) expected from the minor allele frequency 0.470 (p=0.000014). This deviation was not observed in 549 middle-aged (18-50. years) controls (270 (49%) heterozygotes observed vs. 274 (50%) expected; minor allele frequency 0.475; p=0.743). Unfavorable significance of CASP5 heterozygous genotype may be explained by the role of the caspase-5 in inflammation-related processes. Almost all prior gene-longevity association studies focused on discrimination between "good" and "bad" gene variants. Here we present a distinct situation, where the combination of alternative alleles (i.e., heterozygosity) appears to be unfavorable as compared to the homozygous carriership of either gene variant. © 2010 Elsevier Inc.


Kuligina E.S.,Nn Petrov Institute Of Oncology | Sokolenko A.P.,St Petersburg Pediatric Medical Academy | Mitiushkina N.V.,Nn Petrov Institute Of Oncology | Abysheva S.N.,Nn Petrov Institute Of Oncology | And 10 more authors.
Familial Cancer | Year: 2013

Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515-2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02-4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515-2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel-Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups. © 2012 Springer Science+Business Media Dordrecht.

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