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1.  Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study 
Jakubowska, A | Rozkrut, D | Antoniou, A | Hamann, U | Scott, R J | McGuffog, L | Healy, S | Sinilnikova, O M | Rennert, G | Lejbkowicz, F | Flugelman, A | Andrulis, I L | Glendon, G | Ozcelik, H | Thomassen, M | Paligo, M | Aretini, P | Kantala, J | Aroer, B | von Wachenfeldt, A | Liljegren, A | Loman, N | Herbst, K | Kristoffersson, U | Rosenquist, R | Karlsson, P | Stenmark-Askmalm, M | Melin, B | Nathanson, K L | Domchek, S M | Byrski, T | Huzarski, T | Gronwald, J | Menkiszak, J | Cybulski, C | Serrano, P | Osorio, A | Cajal, T R | Tsitlaidou, M | Benítez, J | Gilbert, M | Rookus, M | Aalfs, C M | Kluijt, I | Boessenkool-Pape, J L | Meijers-Heijboer, H E J | Oosterwijk, J C | van Asperen, C J | Blok, M J | Nelen, M R | van den Ouweland, A M W | Seynaeve, C | van der Luijt, R B | Devilee, P | Easton, D F | Peock, S | Frost, D | Platte, R | Ellis, S D | Fineberg, E | Evans, D G | Lalloo, F | Eeles, R | Jacobs, C | Adlard, J | Davidson, R | Eccles, D | Cole, T | Cook, J | Godwin, A | Bove, B | Stoppa-Lyonnet, D | Caux-Moncoutier, V | Belotti, M | Tirapo, C | Mazoyer, S | Barjhoux, L | Boutry-Kryza, N | Pujol, P | Coupier, I | Peyrat, J-P | Vennin, P | Muller, D | Fricker, J-P | Venat-Bouvet, L | Johannsson, O Th | Isaacs, C | Schmutzler, R | Wappenschmidt, B | Meindl, A | Arnold, N | Varon-Mateeva, R | Niederacher, D | Sutter, C | Deissler, H | Preisler-Adams, S | Simard, J | Soucy, P | Durocher, F | Chenevix-Trench, G | Beesley, J | Chen, X | Rebbeck, T | Couch, F | Wang, X | Lindor, N | Fredericksen, Z | Pankratz, V S | Peterlongo, P | Bonanni, B | Fortuzzi, S | Peissel, B | Szabo, C | Mai, P L | Loud, J T | Lubinski, J
British Journal of Cancer  2012;106(12):2016-2024.
The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.
To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.
There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.
The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
PMCID: PMC3388557  PMID: 22669161
BRCA1/2 mutation carriers; PHB 1630 C>T polymorphism; MTHFR 677 C>T polymorphism; breast/ovarian cancer risk
2.  Genetic polymorphisms in fatty acid metabolism genes and colorectal cancer 
Mutagenesis  2012;27(2):169-176.
Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included dietary fat intake; consequently, the role of genes in the fatty acid biosynthesis and metabolism pathways is of particular interest. Moreover, hyperlipidaemia has been associated with different type of cancer and serum lipid levels could be affected by genetic factors, including polymorphisms in the lipid metabolism pathway. The aim of this study is to assess the association between single-nucleotide polymorphisms (SNPs) in fatty acid metabolism genes, serum lipid levels, body mass index (BMI) and dietary fat intake and CRC risk; 30 SNPs from 8 candidate genes included in fatty acid biosynthesis and metabolism pathways were genotyped in 1780 CRC cases and 1864 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. Several LIPC (lipase, hepatic) polymorphisms were found to be associated with CRC risk, although no particular haplotype was related to CRC. The SNP rs12299484 showed an association with CRC risk after Bonferroni correction. We replicate the association between the T allele of the LIPC SNP rs1800588 and higher serum high-density lipoprotein levels. Weak associations between selected polymorphism in the LIPC and PPARG genes and BMI were observed. A path analysis based on structural equation modelling showed a direct effect of LIPC gene polymorphisms on colorectal carcinogenesis as well as an indirect effect mediated through serum lipid levels. Genetic polymorphisms in the hepatic lipase gene have a potential role in colorectal carcinogenesis, perhaps though the regulation of serum lipid levels.
PMCID: PMC3269001  PMID: 22294764
3.  Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population 
Annals of Oncology  2010;22(4):964-966.
Background: The frequency and characteristics of disease in individuals who concomitantly harbor pathogenic mutations in both BRCA1 and BRCA2 genes are not established.
Materials and methods: Data were collected from the database of Clalit Health Services National Familial Cancer Consultation Service. Probands referred to this clinical service and their family members are routinely tested for the three Jewish founder mutations (BRCA1:185delAG, 5382insC, BRCA2:6174delT). In addition, carriers identified in a population-based cohort of all cases diagnosed with breast cancer in Israel in 1987–1988 allowed the estimation of the population frequency of this phenomenon.
Results: In the clinic-based series of 1191 carriers of mutations in BRCA1 or BRCA2 belonging to 567 families, 22 males and females (1.85%) from 17 different families (3.0%) were found to harbor two different mutations. These included 18 individuals (1.51%) who concomitantly carried the 185delAG BRCA1 and the 6174delT BRCA2 mutations and four individuals (0.34%) who carried the 5382insC BRCA1 and the 6174delT mutations. All individuals were heterozygote carriers and none had a double mutation of both founder mutations in the BRCA1 gene itself. Seven of the 16 double carrier women (46.7%) had a personal history of breast carcinoma, diagnosed at a mean age of 44.6, compared with 372/926 (40.2%) carriers of a single mutation diagnosed with a mean age at diagnosis of 48.1 [odds ratio (OR) = 1.3, 95% confidence interval (CI) 0.4–4.0]. One case (6.7%) had a personal history of ovarian carcinoma diagnosed at the age of 53 compared with 55/926 (5.9%) of the women with single mutation (OR = 1.1, CI = 0.2–7.6). The frequency of double mutations in the population-based national breast cancer cohort was 2.2% of all carriers, and 0.3% of all breast cancer cases in the Ashkenazi population in the cohort. The mean age at diagnosis of breast cancer was younger in the carriers of two mutations.
Conclusion: Double carriers of mutations in the BRCA genes are rare and seem to be carrying a similar probability of developing breast and ovarian cancers as carriers of single mutations.
PMCID: PMC3065879  PMID: 20924075
Ashkenazi Jewish women; BRCA; double mutations
4.  Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) 
Osorio, A | Milne, R L | Pita, G | Peterlongo, P | Heikkinen, T | Simard, J | Chenevix-Trench, G | Spurdle, A B | Beesley, J | Chen, X | Healey, S | Neuhausen, S L | Ding, Y C | Couch, F J | Wang, X | Lindor, N | Manoukian, S | Barile, M | Viel, A | Tizzoni, L | Szabo, C I | Foretova, L | Zikan, M | Claes, K | Greene, M H | Mai, P | Rennert, G | Lejbkowicz, F | Barnett-Griness, O | Andrulis, I L | Ozcelik, H | Weerasooriya, N | Gerdes, A-M | Thomassen, M | Cruger, D G | Caligo, M A | Friedman, E | Kaufman, B | Laitman, Y | Cohen, S | Kontorovich, T | Gershoni-Baruch, R | Dagan, E | Jernström, H | Askmalm, M S | Arver, B | Malmer, B | Domchek, S M | Nathanson, K L | Brunet, J | Ramón y Cajal, T | Yannoukakos, D | Hamann, U | Hogervorst, F B L | Verhoef, S | García, EB Gómez | Wijnen, J T | van den Ouweland, A | Easton, D F | Peock, S | Cook, M | Oliver, C T | Frost, D | Luccarini, C | Evans, D G | Lalloo, F | Eeles, R | Pichert, G | Cook, J | Hodgson, S | Morrison, P J | Douglas, F | Godwin, A K | Sinilnikova, O M | Barjhoux, L | Stoppa-Lyonnet, D | Moncoutier, V | Giraud, S | Cassini, C | Olivier-Faivre, L | Révillion, F | Peyrat, J-P | Muller, D | Fricker, J-P | Lynch, H T | John, E M | Buys, S | Daly, M | Hopper, J L | Terry, M B | Miron, A | Yassin, Y | Goldgar, D | Singer, C F | Gschwantler-Kaulich, D | Pfeiler, G | Spiess, A-C | Hansen, Thomas v O | Johannsson, O T | Kirchhoff, T | Offit, K | Kosarin, K | Piedmonte, M | Rodriguez, G C | Wakeley, K | Boggess, J F | Basil, J | Schwartz, P E | Blank, S V | Toland, A E | Montagna, M | Casella, C | Imyanitov, E N | Allavena, A | Schmutzler, R K | Versmold, B | Engel, C | Meindl, A | Ditsch, N | Arnold, N | Niederacher, D | Deißler, H | Fiebig, B | Varon-Mateeva, R | Schaefer, D | Froster, U G | Caldes, T | de la Hoya, M | McGuffog, L | Antoniou, A C | Nevanlinna, H | Radice, P | Benítez, J
British Journal of Cancer  2009;101(12):2048-2054.
In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.
We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.
We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers.
This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
PMCID: PMC2795432  PMID: 19920816
BRCA1; BRCA2; ERCC4; breast cancer
5.  The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers 
British Journal of Cancer  2009;101(8):1456-1460.
The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.
To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.
No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, Ptrend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, Ptrend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, Ptrend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, Ptrend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.
There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.
PMCID: PMC2768437  PMID: 19707196
TP53; MDM2; BRCA1/2; breast cancer; polymorphism; risk
6.  Distinct sensitivity of normal and malignant cells to ultrasound in vitro. 
Environmental Health Perspectives  1997;105(Suppl 6):1575-1578.
The effect of ultrasonic irradiation on the viability of human normal (foreskin fibroblast and amniotic fluid epithelial) and tumor (breast carcinoma, melanoma, and lung carcinoma) cells lines was studied. Cells were subjected to ultrasonic irradiation with a frequency of 20 kHz and an intensity of 0.33 W/cm2 for variable periods of time. Several parameters were tested to determine the effects of ultrasonic irradiation on cell viability and cellular function. Normal cells were relatively resistant to ultrasonic irradiation, whereas malignant cells were much more sensitive. Maximum damage occurred 4 min after exposure of the malignant cells to irradiation. Cellular DNA and protein synthesis were significantly affected as a function of time of irradiation and cloning efficiency of malignant cells exposed to irradiation was greatly reduced. To generalize the consistency of the ultrasonic effect, studies on additional normal and malignant human cells of distinct origin are under way to test their sensitivity to ultrasonic irradiation. Thus, the applicability of ultrasonic irradiation as an antitumor agent may be important in the development of a new methodology in the treatment of cancer.
PMCID: PMC1469937  PMID: 9467085
7.  La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. 
Journal of Virology  1993;67(7):3798-3807.
Translation initiation on poliovirus RNA occurs by internal binding of ribosomes to a sequence within the 5' untranslated region. We have previously characterized a HeLa cell protein, p52, that binds to a fragment of the poliovirus 5' untranslated region (K. Meerovitch, J. Pelletier, and N. Sonenberg, Genes Dev. 3:1026-1034, 1989). Here we report the purification of the HeLa p52. Protein microsequencing identified p52 as La autoantigen. The La protein is a human antigen that is recognized by antibodies from patients with autoimmune disorders such as systemic lupus erythematosus and Sjögren's syndrome. We show that the La protein stimulates translation of poliovirus RNA, but not brome mosaic virus, tobacco mosaic virus, and alfalfa mosaic virus 4 RNA, translation in a reticulocyte lysate. In addition, La corrects aberrant translation of poliovirus RNA in a reticulocyte lysate. Subcellular immunolocalization showed that La protein is mainly nuclear, but after poliovirus infection, La is redistributed to the cytoplasm. Our results suggest that La protein is involved in poliovirus internal initiation of translation and might function through a similar mechanism in the translation of cellular mRNAs.
PMCID: PMC237744  PMID: 8389906

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