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ABSTRACT: BACKGROUND: The RNase III enzyme DICER1 plays a central role in maturation of microRNAs. Identification of neoplasia-associated germ-line and somatic mutations in DICER1 indicates that mis-expression of miRNAs in cancer may result from defects in their processing. As part of a recent study of DICER1 RNase III domains in 96 testicular germ cell tumors, a single RNase IIIb domain mutation was identified in a seminoma. To further explore the importance of DICER1 mutations in the etiology of testicular germ cell tumors (TGCT), we studied germ-line DNA samples from 43 probands diagnosed with familial TGCT. FINDINGS: We carried out High Resolution Melting Curve Analysis of DICER1 exons 2--12, 14--19, 21 and 24--27. All questionable melt curves were subjected to confirmatory Sanger sequencing.Sanger sequencing was used for exons 13, 20, 22 and 23. Intron-exon boundaries were included in all analyses. We identified 12 previously reported single nucleotide polymorphisms and two novel single nucleotide variants. No likely deleterious variants were identified; notably no mutations that were predicted to truncate the protein were identified. CONCLUSIONS: Taken together with previous studies, the findings reported here suggest a very limited role for either germ-line or somatic DICER1 mutations in the etiology of TGCT.
BMC Research Notes 04/2013; 6(1):127.
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William D Foulkes,
Amin Bahubeshi,
Nancy Hamel,
Barbara Pasini,
Sofia Asioli,
Gareth Baynam,
Catherine S Choong,
Adrian Charles,
Richard P Frieder,
Megan K Dishop,
Nicole Graf,
Mesiha Ekim,
Dorothée Bouron-Dal Soglio,
Jocelyne Arseneau,
Robert H Young,
Nelly Sabbaghian,
Archana Srivastava, Marc D Tischkowitz,
John R Priest
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ABSTRACT: DICER1 is crucial for embryogenesis and early development. Forty different heterozygous germline DICER1 mutations have been reported worldwide in 42 probands that developed as children or young adults, pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian sex cord-stromal tumors (especially Sertoli-Leydig cell tumor [SLCT]), and/or multinodular goiter (MNG). We report DICER1 mutations in seven additional families that manifested uterine cervix embryonal rhabdomyosarcoma (cERMS, four cases) and primitive neuroectodermal tumor (cPNET, one case), Wilms tumor (WT, three cases), pulmonary sequestration (PS, one case), and juvenile intestinal polyp (one case). One carrier developed (age 25 years) a pleomorphic sarcoma of the thigh; another carrier had transposition of great arteries (TGA). These observations show that cERMS, cPNET, WT, PS, and juvenile polyps fall within the spectrum of DICER1-related diseases. DICER1 appears to be the first gene implicated in the etiology of cERMS, cPNET, and PS. Young adulthood sarcomas and perhaps congenital malformations such as TGA may also be associated.
Human Mutation 08/2011; 32(12):1381-4. · 5.69 Impact Factor
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Thomas Rio Frio,
Josée Lavoie,
Nancy Hamel,
Felipe C Geyer,
Yaël B Kushner,
David J Novak,
Landon Wark,
Cristian Capelli,
Jorge S Reis-Filho,
Sabine Mai,
Tomi Pastinen, Marc D Tischkowitz,
Victoria A Marcus,
William D Foulkes
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ABSTRACT: A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).
New England Journal of Medicine 12/2010; 363(27):2628-37. · 53.30 Impact Factor
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ABSTRACT: Six genes confer a high risk for developing breast cancer (BRCA1/2, TP53, PTEN, STK11, CDH1). Both BRCA1 and BRCA2 have DNA repair functions, and BRCA1/2 deficient tumors are now being targeted by poly(ADP-ribose) polymerase inhibitors. Other genes conferring an increased risk for breast cancer include ATM, CHEK2, PALB2, BRIP1 and genome-wide association studies have identified lower penetrance alleles including FGFR2, a minor allele of which is associated with breast cancer. We review recent findings related to the function of some of these genes, and discuss how they can be targeted by various drugs. Gaining deeper insights in breast cancer susceptibility will improve our ability to identify those families at increased risk and permit the development of new and more specific therapeutic approaches.
Human Genetics 09/2008; 124(1):31-42. · 5.07 Impact Factor
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Marc D Tischkowitz,
Ahmet Yilmaz,
Long Q Chen,
Danielle M Karyadi,
David Novak,
Tomas Kirchhoff,
Nancy Hamel,
Sean V Tavtigian,
Suzanne Kolb,
Tarek A Bismar, [......],
Peter S Nelson,
Lee Hood,
Steven A Narod,
Kirsten A White,
Elaine A Ostrander,
William B Isaacs,
Kenneth Offit,
Kathleen A Cooney,
Janet L Stanford,
William D Foulkes
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ABSTRACT: Checkpoint kinase 2 (CHEK2) is a protein involved in arresting cell cycle in response to DNA damage. To investigate whether it plays an important role in the development of prostate cancer (PRCA) in the Ashkenazi Jewish (AJ) population, we sequenced CHEK2 in 75 AJ individuals with prostate, breast, or no cancer (n=25 each). We identified seven coding SNPs (five are novel) that changed the amino-acid sequence, resulting in R3W, E394F, Y424H, S428F, D438Y, P509S, and P509L. We determined the frequency of each variant in 76 AJ families collected by members of the International Consortium for Prostate Cancer Genetics (ICPCG) where >or=2 men were affected by PRCA. Only one variant, Y424H in exon 11, was identified in more than two families. Exon 11 was then screened in nine additional AJ ICPCG families (a total of 85 families). The Y424H variant occurred in nine affected cases from four different families; however, it did not completely segregate with the disease. We performed bioinformatics analysis, which showed that Y424H is a non-conservative missense substitution that falls at a position that is invariant in vertebrate CHEK2 orthologs. Both SIFT and Align-GVGD predict that Y424H is a loss of function mutation. However, the frequency of Y424H was not significantly different between unselected AJ cases from Montreal/Memorial Sloan Kettering Cancer Centre (MSKCC) and AJ controls from Israel/MSKCC (OR 1.18, 95%CI: 0.34-4.61, p=.99). Moreover, functional assays using Saccharomyces cerevisiae revealed that the Y424H substitution did not alter function of CHEK2 protein. Although we cannot rule out a subtle influence of the CHEK2 variants on PRCA risk, these results suggest that germline CHEK2 mutations have a minor role in, if any, PRCA susceptibility in AJ men.
Cancer letters 07/2008; 270(1):173-80. · 4.86 Impact Factor
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ABSTRACT: Many BRCA1-related tumors have a distinct histological characteristics which together have been called "basal-like." Typically such tumors are ER-, HER2- and express cytokeratin 5/6, cytokeratin 8/18, EGFR and vimentin. These characteristics can be used to predict which breast cancers are most likely to be associated with germline BRCA1 mutations which has important implications for breast pathologists. Moreover, BRCA1-related breast cancers generally have a poorer prognosis which may paradoxically be more pronounced in node negative cancers. This may relate in part to a different pattern of metastatic spread with in increased frequency of brain and lung metastases in BRCA1 carriers. Conversely, BRCA1-related tumors may respond better to neoadjuvant chemotherapy and their characteristic molecular signature may provide opportunities to develop specific molecular targeted therapies akin to traztuzumab in HER2+ cancers. Finally, many of the phenotypic features of BRCA1-related tumors might also be found in putative breast stem cells and therefore characterization of the BRCA1 breast cancer phenotype will improve our understanding of sporadic breast carcinogenesis.
Cell cycle (Georgetown, Tex.) 06/2006; 5(9):963-7. · 5.36 Impact Factor
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Elsa Callén,
José A Casado, Marc D Tischkowitz,
Juan A Bueren,
Amadeu Creus,
Ricard Marcos,
Angeles Dasí,
Jesús M Estella,
Arturo Muñoz,
Juan J Ortega,
Johan de Winter,
Hans Joenje,
Detlev Schindler,
Helmut Hanenberg,
Shirley V Hodgson,
Christopher G Mathew,
Jordi Surrallés
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ABSTRACT: Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and cancer predisposition. Here we have identified Spanish Gypsies as the ethnic group with the world's highest prevalence of FA (carrier frequency of 1/64-1/70). DNA sequencing of the FANCA gene in 8 unrelated Spanish Gypsy FA families after retroviral subtyping revealed a homozygous FANCA mutation (295C>T) leading to FANCA truncation and FA pathway disruption. This mutation appeared specific for Spanish Gypsies as it is not found in other Gypsy patients with FA from Hungary, Germany, Slovakia, and Ireland. Haplotype analysis showed that Spanish Gypsy patients all share the same haplotype. Our data thus suggest that the high incidence of FA among Spanish Gypsies is due to an ancestral founder mutation in FANCA that originated in Spain less than 600 years ago. The high carrier frequency makes the Spanish Gypsies a population model to study FA heterozygote mutations in cancer.
Blood 03/2005; 105(5):1946-9. · 9.90 Impact Factor
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ABSTRACT: Fanconi anemia is a chromosomal instability syndrome associated with certain congenital abnormalities, defective hemopoiesis, and an increased risk of developing acute myeloid leukemia and some solid tumors. The diagnosis can be made at birth if congenital abnormalities are present but is often made in childhood when hematologic complications develop. The authors report a case of Fanconi anemia diagnosed in a child with no congenital abnormalities and normal bone marrow who first presented with a cerebellar medulloblastoma. The authors discuss diagnostic and therapeutic implications for such malignancies in Fanconi anemia.
Journal of Pediatric Hematology/Oncology 02/2004; 26(1):52-5. · 1.16 Impact Factor
