Increased frequency of disease-causing MYH mutations in colon cancer families

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Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

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)

Background: 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. Methods: 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. Results: 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. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families

Background: The estimated ratio of hereditary breast/ovarian cancer (HBOC) based on family history is 1.5% in Latvia. This is significantly lower than the European average of 5-10%. Molecular markers like mutations and SNPs can help distinguish HBOC patients in the sporadic breast and ovarian cancer group.Methods: 50 patients diagnosed with HBOC in the Latvian Cancer Registry from January 2005 to December 2008 were screened for BRCA1 founder mutation-negatives and subjected to targeted resequencing of BRCA1 and BRCA2 genes. The newly found mutations were screened for in the breast and ovarian cancer group of 1075 patients by Real Time-PCR/HRM analysis and RFLP.Results: Four BRCA2 mutations including three novel BRCA2 frameshift mutations and one previously known BRCA2 frameshift mutation and one BRCA1 splicing mutation were identified. Two of the BRCA2 mutations were found in a group of consecutive breast cancer patients with a frequency of 0.51% and 0.38%.Conclusions: Molecular screening of sequential cancer patients is an important tool to identify HBOC families.publishersversionPeer reviewe

Personalized medicine: new genomics, old lessons

Personalized medicine uses traditional, as well as emerging concepts of the genetic and environmental basis of disease to individualize prevention, diagnosis and treatment. Personalized genomics plays a vital, but not exclusive role in this evolving model of personalized medicine. The distinctions between genetic and genomic medicine are more quantitative than qualitative. Personalized genomics builds on principles established by the integration of genetics into medical practice. Principles shared by genetic and genomic aspects of medicine, include the use of variants as markers for diagnosis, prognosis, prevention, as well as targets for treatment, the use of clinically validated variants that may not be functionally characterized, the segregation of these variants in non-Mendelian as well as Mendelian patterns, the role of gene–environment interactions, the dependence on evidence for clinical utility, the critical translational role of behavioral science, and common ethical considerations. During the current period of transition from investigation to practice, consumers should be protected from harms of premature translation of research findings, while encouraging the innovative and cost-effective application of those genomic discoveries that improve personalized medical care

Frequency of CHEK2 mutations in a population based, case–control study of breast cancer in young women

INTRODUCTION: The cell-cycle checkpoint kinase (CHEK)2 protein truncating mutation 1100delC has been associated with increased risk for breast or prostate cancer. Multiple studies have found an elevated frequency of the 1100delC variant in specific stratifications of breast cancer patients with a family history of the disease, including BRCA1/BRCA2 negative families and families with a history of bilateral disease or male breast cancer. However, the 1100delC mutation has only been investigated in a few population-based studies and none from North America. METHODS: We report here on the frequency of three CHEK2 variants that alter protein function – 1100delC, R145W, and I175T – in 506 cases and 459 controls from a population based, case–control study of breast cancer conducted in young women from western Washington. RESULTS: There was a suggestive enrichment in the 1100delC variant in the cases (1.2%) as compared with the controls (0.4%), but this was based on small numbers of carriers and the differences were not statistically significant. The 1100delC variant was more frequent in cases with a first-degree family history of breast cancer (4.3%; P = 0.02) and slightly enriched in cases with a family history of ovarian cancer (4.4%; P = 0.09). CONCLUSION: The CHEK2 variants are rare in the western Washington population and, based on accumulated evidence across studies, are unlikely to be major breast cancer susceptibility genes. Thus, screening for the 1100delC variant may have limited usefulness in breast cancer prevention programs in the USA

Bringing the Street Back In:Considering Strategy, Contingency and Relative Good Fortune in Street Children’s Access to Paid Work in Accra

A sociology of street children has emerged defined by its rejection of the dominant narratives of child welfare organisations that identify the street as the root cause of children’s immiseration and improper socialisation. In its place, sociological analysis has undermined the value of conceptualising street children as a coherent group on the street and in a parallel move has looked to conceptually reposition street children away from assumptions of passivity and neglect, towards a foundational insistence that the starting place for analysis is the positioning of street children as active and strategic social agents. It is the adequacy of this latter concern that is the focus of this article. By reintroducing the location of children within the social relations of the informal street economy, this article draws upon extensive and long-term qualitative research examining the lives of street children in Accra, Ghana. The argument here is that sociological notions of strategic action and efficacious agency seem ill-suited to accounting for the dilemmas and difficulties that street children’s quests for paid work inevitably involve. Rather, it is relative good fortune within the radical uncertainty of the social relations of the informal street economy that seems much more appropriate to accounting for how these children are integrated into wor