annual report january 2008 to december 2008 program in cancer

Program in Cancer Genetics, McGill University

Annual Report January 2008 to December 2008

Program in Cancer Genetics Departments of Oncology and Human Genetics

McGill University www.mcgill.ca/cancergenetics/

The Program in Cancer Genetics is grateful to receive funding from the Turner Family Cancer Research Fund.

MEMBERS William D Foulkes MB, PhD (Director, Hereditary Cancer) Patricia Tonin PhD (Ovarian Cancer, Hereditary Breast/Ovarian Cancer) Ala-Eddin Al Moustafa PhD (HPV/gene cooperation in head and neck, cervical and breast cancers) Marc Tischkowitz MD, PhD (Human Genetics, Hereditary Cancer) Tarek Bismar MD (Pathology) (Adjunct, now at University of Calgary) Raquel Aloyz PhD (Molecular and Cellular Biology, Oncology) Sabrina Notte BAA (Program coordinator) Jean-Sébastien Brunet MSc (Statistical Consultant) SUMMARY AND HIGHLIGHTS The year 2008 saw one important change – Dr. Tarek Bismar accepted a position at the University of Calgary, but remains an adjunct member of the program. The highlights for 2008 were as follows – Dr. Tischkowitz was awarded a Komen Grant to further study the genetics and his student, David Novak, won a MCETC/CIHR studentship for his work on PALB2. Dr Tischkowitz published several papers on BRCA1/2-related proteins such as PALB2, RAP80 and Abraxas. Dr. Tonin’s research group continued to make progress in the characterization of molecular genetic markers for ovarian cancer, the role of chromosome 3 and 17 genes in ovarian cancer, and further defined the contribution of known genetic factors in inherited predisposition to breast and ovarian cancer in the French Canadian population of Quebec. Dr Foulkes published a review of inherited susceptibility to the common cancers in the New England Journal of Medicine. In his lab, Dr Foulkes’ group continue to focus on working with families that may provide new etiological clues. As well as a specific study of one interesting variant in BRCA1, he was an author on a series of papers on unclassified variants (published in a special edition of Human Mutation), following a meeting at IARC in 2007. His PhD student Kristi Baker completed her thesis and started her post-graduate work at Harvard.

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http://www.mcgill.ca/cancergenetics/


2008 PUBLICATIONS (highlighted publications supported by Turner Family Cancer Research Fund)

Peer Reviewed Papers 1. Arcand SL, Maugard CM, Ghadirian P, Robidoux A, Perret C, Zhang P, Fafard E, Mes-

Masson AM, Foulkes WD, Provencher D, Narod SA, Tonin PN. Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. Breast Cancer Res Treat. 108(3):399-408, 2008.

2. Foulkes WD. BRCA1-sowing the seeds crooked in the furrow. Nat Genet., 40(1):8-9, 2008.

3. Metcalfe KA, Lubinski J, Ghadirian P, Lynch H, Kim-Sing C, Friedman E, Foulkes WD, Domchek S, Ainsworth P, Isaacs C, Tung N, Gronwald J, Cummings S, Wagner T, Manoukian S, Møller P, Weitzel J, Sun P, Narod SA. Predictors of Contralateral Prophylactic Mastectomy in Women with a BRCA1 or BRCA2 Mutation: The Hereditary Breast Cancer Clinical Study Group. J Clin Oncol. 26(7):1093-7, 2008.

4. Metcalfe KA, Birenbaum-Carmeli D, Lubinski J, Gronwald J, Lynch H, Ghadirian P, Foulkes WD, Klijn J, Friedman E, Kim-Sing C, Ainsworth P, Rosen B, Domchek S, Wagner T, Tung N, Manoukian S, Couch F, Sun P, Narod SA and the Hereditary Breast Cancer Clinical Study Group Breast. International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer 122(9):2017-22, 2008.

5. Tischkowitz M, Sabbaghian N, Ray AM, Lange EM, Foulkes WD, Cooney KA. Analysis of the Gene Coding for the BRCA2-Interacting Protein PALB2 in Hereditary Prostate Cancer. The Prostate, 68(6):675-8, 2008.

6. Tischkowitz M, Hamel N, Carvalho MA, Birrane G, Soni A, van Beers EH, Joosse SA, Wong N, Novak D, Quenneville LA, Grist S, kConFab, Nederlof PM, Goldgar DE, Tavtigian SV, Monteiro ANA, Ladias JAA, Foulkes WD. Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket – a multi-modal approach. Eur J Hum Genet., 16(7):820-32, 2008.

7. Hamel N, Tischkowitz M, Foulkes WD. [A role for PALB2/FANCN in breast cancer predisposition?] Med Sci (Paris). 24(2):120-1, 2008.

8. Metcalfe KA, Foulkes WD, Kim-Sing C, Ainsworth P, Rosen B, Armel S, Poll A, Eisen A, Gilchrist D, Chudley A, Ghadirian P, Maugard C, Lemire EG, Sun P, Narod S. A family history as a predictor of uptake of cancer preventive procedures by women with a BRCA1 or BRCA2 mutation. Clin Genet, 73(5):474-9, 2008.

9. Vu TT, Zeitouni AG, Tsinalis P, Foulkes WD, Hagr A. Familial clustering of parotid gland lymphoepithelioma in North America. J Otolaryngol., 37(1):23-6, 2008.

10. Ginsburg O, Ghadirian P, Lubinski J, Cybulski C, Lynch H, Neuhausen S, Kim-Sing C, Robson M, Domchek S, Isaacs C, Klijn J, Armel S, Foulkes WD, Tung N, Moller P, Sun P, Narod SA; Hereditary Breast Cancer Clinical Study Group. Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: an update. Breast Cancer Res Treat. 2008 May 16. [Epub ahead of print]

11. Baker K, Foulkes WD, Jass JR. MSI-H colorectal cancers preferentially retain and expand intraepithelial lymphocytes rather than peripherally derived CD8(+) T cells. Cancer Immunol Immunother. 2008 May 17. [Epub ahead of print]

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12. Varela-Lema L, Taioli E, Ruano-Ravina A, Barros-Dios JM, Anantharaman D, Benhamou S, Boccia S, Bhisey RA, Cadoni G, Capoluongo E, Chen CJ, Foulkes WD, Goloni-Bertollo EM, Hatagima A, Hayes RB, Katoh T, Koifman S, Lazarus P, Manni JJ, Mahimkar M, Park J, Park KK, Pavarino Bertelli EC, de Souza Fonseca Ribeiro EM, Roy B, Spitz MR, Strange RC, Wei Q, Ragin CC. Meta-analysis and pooled analysis of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers: a HuGE-GSEC review. Genet Med. 10(6):369-84, 2008.

13. Kotsopoulos J, Librach CL, Lubinski J, Gronwald J, Kim-Sing C, Ghadirian P, Lynch HT, Moller P, Foulkes WD, Randall S, Manoukian S, Pasini B, Tung N, Ainsworth PJ, Cummings S, Sun P, Narod SA; Hereditary Breast Cancer Clinical Study Group. Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case-control study. Cancer Causes Control. 19(10):1111-9, 2008 .

14. Tischkowitz MD, Yilmaz A, Chen LQ, Karyadi DM, Novak D, Kirchhoff T, Hamel N, Tavtigian SV, Kolb S, Bismar TA, Aloyz R, Nelson PS, Hood L, Narod SA, White KA, Ostrander EA, Isaacs WB, Offit K, Cooney KA, Stanford JL, Foulkes WD. Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer. Cancer Lett., 270(1):173-1780, 2008.

15. Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum Genet., 124(1):31-42, 2008.

16. Narod SA, Neuhausen S, Vichodez G, Armel S, Lynch HT, Ghadirian P, Cummings S, Olopade O, Stoppa-Lyonnet D, Couch F, Wagner T, Warner E, Foulkes WD, Saal H, Weitzel J, Tulman A, Poll A, Nam R, Sun P. Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer, 99(2):371-4, 2008.

17. Foulkes WD, Grainge MJ, Rakha EA, Green AR, Ellis IO. Tumor size is an unreliable predictor of prognosis in basal-like breast cancers and does not correlate closely with lymph node status. Breast Cancer Res Treat. 2008 Jul 4. [Epub ahead of print]

18. Voduc D, Nielsen TO, Cheang MC, Foulkes WD. The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype. Hum Pathol. 39(10):1431-7, 2008.

19. Kote-Jarai Z, Easton DF, Stanford JL, Ostrander EA, Schleutker J, Ingles SA, Schaid D, Thibodeau S, Dörk T, Neal D, Cox A, Maier C, Vogel W, Guy M, Muir K, Lophatananon A, Kedda MA, Spurdle A, Steginga S, John EM, Giles G, Hopper J, Chappuis PO, Hutter P, Foulkes WD, Hamel N, Salinas CA, Koopmeiners JS, Karyadi DM, Johanneson B, Wahlfors T, Tammela TL, Stern MC, Corral R, McDonnell SK, Schürmann P, Meyer A, Kuefer R, Leongamornlert DA, Tymrakiewicz M, Liu JF, O'Mara T, Gardiner RA, Aitken J, Joshi AD, Severi G, English DR, Southey M, Edwards SM, Al Olama AA; The PRACTICAL Consortium, Eeles RA. Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium. Cancer Epidemiol Biomarkers Prev. 17(8):2052-2061, 2008.

20. Novak DJ, Chen LQ, Ghadirian P, Hamel N, Zhang P, Rossiny V, Cardinal G, Robidoux A, Tonin PN, Rousseau F, Narod SA, Foulkes WD. Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women. BMC Cancer. 8(1):239, 2008.

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21. Novak DJ, Sabbaghian N, Maillet P, Chappuis PO, Foulkes WD, Tischkowitz M. Analysis of the genes coding for the BRCA1-interacting proteins, RAP80 and Abraxas (CCDC98), in high-risk, non-BRCA1/2, multiethnic breast cancer cases. Breast Cancer Res Treat. 2008 Aug 10. [Epub ahead of print]

22. Arnes JB, Bégin LR, Stefansson IM, Brunet JS, Nielsen TO, Foulkes WD, Akslen LA. Expression of EGFR in relation to BRCA1 status, basal-like markers and prognosis in breast cancer. J Clin Pathol. 2008 Aug 4. [Epub ahead of print]

23. Zauber P, Sabbath-Solitare M, Stephen PM, Chamberlain R, Chong G, Foulkes WD, Bishop T. Sporadic desmoid tumor in an Ashkenazi patient homozygous for the APC*I1307K gene mutation. Acta Oncol. 47(6):1158-61, 2008.

24. Palma L, Marcus V, Gilbert L, Chong G, Foulkes WD. Synchronous occult cancers of the endometrium and fallopian tube in an MSH2 mutation carrier at time of prophylactic surgery. Gynecol Oncol. 111(3):575-8, 2008.

25. Scott RH, Douglas J, Baskcomb L, Huxter N, Barker K, Hanks S, Craft A, Gerrard M, Kohler JA, Levitt GA, Picton S, Pizer B, Ronghe MD, Williams D; Factors Associated with Childhood Tumours (FACT) Collaboration, Cook JA, Pujol P, Maher ER, Birch JM, Stiller CA, Pritchard-Jones K, Rahman N, Collaborators: Arbour L, Bonaïti-Pellié C, Cannon-Albright L, Chompret A, Cole T, Dhooge C, Dupuis W, Foot A, Foulkes W, Galvin H, Gnekow A, Graf N, King D, Kingston J, Lewis I, Millot F, O'Meara A, Price H, Royer-Pokora B, Schumacher V, Schwartz C, Shannon R, Sheridan E, Tonin P, Weirih A. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nat Genet. 40(11):1329-34, 2008.

26. Tavtigian SV, Greenblatt MS, Goldgar DE, Boffetta P; IARC Unclassified Genetic Variants Working Group., Collaborators: Boffetta P, Couch F, de Wind N, Easton D, Eccles D, Foulkes W, Genuardi M, Goldgar D, Greenblatt M, Hofstra R, Hogervorst F, Hoogerbrugge N, Plon S, Radice P, Rasmussen L, Sinilnikova O, Spurdle A, Tavtigian S. Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat. 29(11):1261-4, 2008.

27. Greenblatt MS, Brody LC, Foulkes WD, Genuardi M, Hofstra RM, Olivier M, Plon SE, Sijmons RH, Sinilnikova O, Spurdle AB; IARC Unclassified Genetic Variants Working Group. Locus-specific databases and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes. Hum Mutat. 2008 Nov;29(11):1273-81.

28. Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, Hogervorst FB, Hoogerbrugge N, Spurdle AB, Tavtigian SV; IARC Unclassified Genetic Variants Working Group. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 29(11):1282-91, 2008.

29. Hofstra RM, Spurdle AB, Eccles D, Foulkes WD, de Wind N, Hoogerbrugge N, Hogervorst FB; IARC Unclassified Genetic Variants Working Group. Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance. Hum Mutat. 29(11):1292-303, 2008.

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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rahman%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus


30. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med. 13;359(20):2143-53, 2008.

31. Yasmeen A, Liu W, Dekhil H, Kassab A, Aloyz R, Foulkes WD, Al Moustafa AE. BRCA1 mutations contribute to cell motility and invasion by affecting its main regulators. Cell Cycle. 7(23):3781-3, 2008.

32. Schneider BP, Winer EP, Foulkes WD, Garber J, Perou CM, Richardson A, Sledge GW, Carey LA. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res. 14(24):8010-8, 2008.

33. Georgitsi M, Heliövaara E, Paschke R, Kumar AV, Tischkowitz M, Vierimaa O, Salmela P, Sane T, De Menis E, Cannavò S, Gündogdu S, Lucassen A, Izatt L, Aylwin S, Bano G, Hodgson S, Koch CA, Karhu A, Aaltonen LA. Large Genomic Deletions of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene in Pituitary Adenoma Predisposition. J Clin Endocrinol Metab. 93(10):4146-51, 2008.

34. Tischkowitz M, Easton DF, Ball J, Hodgson SV, Mathew CG.Cancer Incidence in Relatives of British Fanconi Anaemia Patients. BMC Cancer. 8(1):257, 2008.

35. Ouellet V, Ling TH, Normandin K, Madore J, Lussier C, Barrès V, Bachvarov D, Rancourt C, Tonin PN, Provencher DM, Mes-Masson AM. Immunohistochemical profiling of benign, low malignant potential and low grade serous epithelial ovarian tumors. BMC Cancer. 8:346, 2008.

36. Cody NA, Zietarska M, Filali-Mouhim A, Provencher DM, Mes-Masson AM, Tonin PN. Influence of monolayer, spheroid, and tumor growth conditions on chromosome 3 gene expression in tumorigenic epithelial ovarian cancer cell lines. BMC Med Genomics. 1:34, 2008.

37. Ouellet V, Zietarska M, Portelance L, Lafontaine J, Madore J, Puiffe ML, Arcand SL, Shen Z, Hébert J, Tonin PN, Provencher DM, Mes-Masson AM. Characterization of three new serous epithelial ovarian cancer cell lines. BMC Cancer. 8:152, 2008.

38. Cavallone L, Arcand SL, Maugard C, Ghadirian P, Mes-Masson AM, Provencher D, Tonin PN. Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent. BMC Cancer. 8:96, 2008.

39. Le Page C, Ouellet V, Quinn MC, Tonin PN, Provencher DM, Mes-Masson AM. BTF4/BTNA3.2 and GCS as candidate mRNA prognostic markers in epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 17(4):913-20, 2008.

40. Wojnarowicz PM, Breznan A, Arcand SL, Filali-Mouhim A, Provencher DM, Mes-Masson AM, Tonin PN. Construction of a chromosome 17 transcriptome in serous ovarian cancer identifies differentially expressed genes. Int J Gynecol Cancer. 18(5):963-75, 2008.

41. Tulandi T, Al-Sunaidi M, Arseneau J, Tonin PN, Arcand SL. Calcified tissue of fetal origin in utero. Fertil Steril. 89(1):217-8, 2008.

42. Birch AH, Quinn MC, Filali-Mouhim A, Provencher DM, Mes-Masson AM, Tonin PN. Transcriptome analysis of serous ovarian cancers identifies differentially expressed chromosome 3 genes. Mol Carcinog. 47(1):56-65, 2008.

43. Amrein L, Hernandez TA, Ferrario C, Johnston J, Gibson SB, Panasci L, Aloyz R. Dasatinib sensitizes primary chronic lymphocytic leukemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol. 143(5):698-706, 2008.

44. Al Moustafa A-E, Kassab A, Darnel A, Yasmeen A. High-risk HPV/ErbB-2 interaction on E-cadherin/catenin regulation in human carcinogenesis. Current Pharmaceutical Design.,14: 2159-2172, 2008.

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45. Akil MN, Darnel A, Yasmeen A, Kassab A, Al Moustafa A-E. Association of Id-1 expression with high-risk human papillomaviruses infection in breast cancer in Syrian woman: a tissue microarray study. British Journal of Cancer, 99: 404-7, 2008.

46. Al Moustafa A-E. Involvement of human papillomavirus infections in prostate cancer progression. Medical Hypotheses Journal, 71: 209-211, 2008.

47. Al Moustafa A-E. Human cervical carcinomas and EGF-R tyrosine kinase inhibitors. Gyn. Oncol. Journal, 109: 308, 2008.

48. Akil N, Kassab A, Yasmeen A, Darnel A, Bismar T, Al Moustafa A-E. Human Breast Cancer and Sexual Activities. British Journal of Cancer, 98: 508-509, 2008.

PATENT

Raquel Aloyz Inventor/Co-inventor. User patent application for the use of Nilotinib® in chronic

lymphocytic leukemia with Lawrence Panasci and Novartis (2008).

GRADUATE STUDENTS SUPERVISED William Foulkes

Name: Lili Li Department: Human Genetics Years: 2007- Degree: PhD Topic: Studies on the regulation of transcription and translation in breast cancer

Patricia Tonin Name: Kathleen Klein Department: Human Genetics Years: 2000-present Degree: MSc (2000-2002); fast track Ph.D. (2002-present)* Year expected: 2009 [*Year leave of absence, maternity leave- May 2007-April 2008] Topic: Is there evidence in favour of novel breast cancer susceptibility alleles in French Canadian hereditary breast-ovarian cancer families? Awards: MUHC Studentship (2001-2002) CIHR Studentship (2002-2005) Name: Neal Cody Department: Human Genetics Years: 2002-present Degree: MSc (2002-2004); fast tract PhD (2004-present) Year expected: 2009 Topic: Characterization of hybrids of ovarian cancer cell line

harbouring a transferred normal human chromosome 3 homologue.

Awards: FGSR Scholarship (2002-2003)

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MUHC Studentship (2003-2004) Name: Paulina Wojnarowicz Department: Human Genetics Years: 2005-present Degree: MSc (2005-2007); fast tract PhD 2007-present Year expected: 2010 Topic: Molecular genetic characterization of RHLBD6 a candidate tumour

suppressor gene in ovarian cancer. Awards: MUHC Studentship (2006-2007) FGSR Prize (2006) NSERC Scholarship (2006-2007) MUHC Studentship (2008-2009) – declined CIHR Studentship (2008-2011) Name: Ashley Bicrh Department: Human Genetics Years: 2005-present Degree: MSc (2005-2007); fast track PhD 2007-present Year expected: 2010 Topic: The chromosome 3 transcriptome in normal and cancerous epithelial

ovarian tissues. Awards: MUHC Studentship (2006-2007; 2007-2008) Dept Medicine Studentship (2006-2007) Name: Vanessa Rossiny Department: Human Genetics Years: 2004-2008 [Includes personal leave of absence] Degree: MSc Year expected: 2008 Topic: Elucidating genetic and epigenetic events associated with chromosome

3p25-pter region in ovarian cancer cell line Awards: MUHC Studentship (2004-2005)

Marc Tischkowitz

Name: David Novak (William Foulkes: co-supervisor) Department: Human Genetics Years: 2007- Degree: MSc Topic: Elucidating the cellular function of breast cancer gene PALB2 Raquel Aloyz

Name: Tayma Khalil (Co-supervision with W. Foulkes) Years: 2007-2008 Degree: MSc

Topic: BRCA1, hCDC4, Cyclin E, and chromosomal instability in breast cancer

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Name: May Shawi (co-supervision with Autexier) Years: 2008- Degree: PhD

Topic: Telomeres and telomerase regulation in CLL: Therapeutic implications UNDERGRADUATE STUDENTS SUPERVISED, INDEPENDENT STUDY Raquel Aloyz

Name: Keira Hodkinson Years: 2008 Topic: Evaluation of the effect of DNA-PK inhibitors on platinum-induced

DNA-damage and cell cycle progression in human colon cancer cells

UNDERGRADUATE MEDICAL STUDENTS SUPERVISED, SUMMER/WINTER BURSARY PROGRAM

Patricia Tonin

Name: Andrea Blotsky Department: Medicine Years: Summer 2008, Fall 2008, Winter 2009

Topic: Genetic analysis of the spectrum of BRCA1 and BRCA2 mutations in French Canadian Breast-Ovarian Cancer families

POSTDOCTORAL TRAINEES William Foulkes

Name: Ahmet Yilmaz Department: Human Genetics Years: 2006-2008 Topic: The molecular genetics of Proteus syndrome Name: Martin Couillard, Ph.D Department: Human Genetics Years: 2008-present Topic: New treatments for genetic diseases Name: Thomas Rio Frio, Ph.D Department: Human Genetics Years: 2008-present

Topic: Identifying new cancer genes

Patricia Tonin Name: Michael Quinn, PhD Department: Human Genetics Years: April 2005-present Topic: Identification of signature pattern of gene expression in ovarian cancer

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using an ovarian cancer model based on functional complementation of chromosome 3 genes.

Name: Luca Cavallone, PhD Department: Human Genetics Years: June 2005 - present Topic: Identification of novel tumour suppressor genes in breast

cancer using the non-sense-mediated decay technique.

Name: Karen Gambaro, PhD Department: Human Genetics Years: April 2007 -present Topic: Characterization of 3p12.3-pcen tumour suppressor candidates in

ovarian cancer using a functional complementation approach based on microcell mediated chromosome transfer techniques.

Raquel Aloyz

Name: Veronica Martinez-Marignac, PhD Years: 2007- present Topic: Role of DNA repair in metastasis

Name: Annette Hollman, PhD Years: 2007- present Topic: New targeted therapies for Lymphoma

Name: David Davidson, PhD Years: 2008- Topic: Synergistic Effect of DNAPK Inhibitors in the Treatment of Cancer

(co-director with Lawrence Panasci) ADVISOR, M.SC. AND PH.D GRADUATE SUPERVISORY COMMITTEES

William Foulkes Name: Timothy Wai Thesis: Mitochondrial DNA and the mammalian oocyte Supervisor: Dr. Eric Shoubridge (Dept. Human Genetics) Date: 2006-current

Name: Carolyn Algire Thesis: The effects of excess energy intake and metformi on tumor growth in

vivo. Supervisor: Dr. Michael Pollak Date: 2006-current Patricia Tonin

Name: Amanda Loewy Thesis: Methylation of the MMACHC promoter in a malignant

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melanoma cell line Supervisor: Dr. David Rosenblatt (Dept. Human Genetics) Date: 2005-2008 Name: Zari Dastani Thesis: Novel genetic determinants of high-density lipoprotein cholesterol

(HDL-C) Supervisor: Jamie Engert, PhD, Jacques Genest, MD

(Dept. Human Genetics) Date: 2005-2009 Name: Ebithaj Bukhari Thesis: In Vitro Analysis of the Functional Consequences of NLRP7

Mutations Supervisor: Rima Slim, PhD (Dept. of Human Genetics) Date: 2007 - 2009

ACADEMIC ADVISOR (CHAIR), DIVISION OF EXPERIMENTAL MEDICINE PH.D. THESIS COMMITTEES Patricia Tonin

Name: Andrea Alter Degree: PhD Supervisor: Irwin Schurr, PhD Date: 2003-2008

Name: Thomas A. Skinner Degree: MSc Supervisor: Danuta Radzioch, PhD Date: 2007 - 2008

Name: Daniel Thiruganaratnapathy Degree: MSc Supervisor: Simone Chevalier, PhD Date: 2007 - 2008

Name: Laure Humbert Degree: PhD Supervisor: Mario Chevrette, PhD Date: 2007- present

EXAMINER OF PH. D. THESES DEFENSE COMMITTEE

Name: Khaldoun Al-Romaih Thesis: Modulation of gene expression in osteosarcoma by

demethylation Supervisor: Jeremy Squire, PhD

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Department of Laboratory Medicine and Pathobiology Faculty of Medicine, University of Toronto

Role: External Examiner Date: April 17, 2008

RESEARCH TECHNICIANS

Nancy Hamel Nelly Sabbaghian Anne Christine Goulett Suzanna Arcand Zhen Shen

Archana Srivastava

TEACHING MCGILL UNIVERSITY

GRADUATE AND UNDERGRADUATE COURSES

William Foulkes

516-614B Environmental Carcinogenesis Department: Medicine (Div. Experimental Medicine) Format: Lecture Title: Cancer Genetics/Prevention Role: Lecturer Level: MSc Program Time: One 2 hour session Years: 1996-1999, 2003, 2005

516-0635D Experimental and Clinical Oncology Department: Medicine Format: Lecture Title: Cancer Genetics Role: Lecturer Level: MSc program Time: 1.5 hour seminar Years: 2002-

521-690B Inherited Cancer Syndrome Department: Department of Human Genetics Format: Lecture Title: Cancer Genetics Role: Lecturer Level: MSc program Time: Four 2 hour sessions Years: 2003, 2005, 2007

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Medical Genetics Unit 8 small group teaching in medical genetics Format: Lecture Role: Lecturer Level: Medical Students Time: One 2 hour lecture and 4 small group sessions, 3 hours each Years: 1977-

Patricia Tonin

Back to basics: Unit 8 - Genetics in Everyday Medicine II Department: Medicine Coordinator: Feigi Kaplan Format: Small group sessions Title: The genetics of inherited adult onset cancer Role: Animator, coordinated sessions on hereditary cancer genetics Level: Second year medical students Time (hrs/yr): 7 hours (Fall sessions) Years: 2008 BOM: Unit 1- Molecules, cells and Tissues Department: Medicine Coordinator: Dr. George Shenouda Format: Small group session Title: Cancer and Oncogenes Role: Animator, coordinated sessions on cancer and oncogenes Level: First year medical students Time (hrs/yr): 2 hours (September session) Years: 2008 EXMD 504A Biology of Cancer Department: Medicine (Division of Experimental Medicine) Coordinator: Dr. David M.P. Thompson Format: Lecture Title: Screening Breast Cancer Genes Role: Lecturer Level: Graduating students and graduate students Time (hr/yr): 2 hrs (Fall Session) Years: 2008

EXMD 635D Experimental & Clinical Oncology Department: Medicine (Div. Experimental Medicine) Coordinator: Dr. Maria Zannis-Hadjopoulos Format: Lecture Title: Cancer Genetics/Prevention Role: Lecturer Level: Graduate students Time (hr/yr): 1.5 hrs

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Years: 2008 (Fall) HGEN 690B Inherited Cancer Syndromes Department: Human Genetics and Medicine (Div. Experimental Medicine) Coordinator: Dr. Patricia Tonin Format: Lecture Role: Coordinator and Lecturer Level: Graduate students (fundamental and genetic counseling), (open to residents as well) Time (hr/yr): 8 hrs (Winter Session/usually alternate years) Years: 2008

Marc Tischkowitz

516-614B Environmental Carcinogenesis Department: Medicine (Div. Experimental Medicine) Format: Lecture Title: It's a dangerous world out there: DNA repair and environmental toxins Role: Lecturer Level: MSc Program Time: One 2 hour session 516-0635D Experimental and Clinical Oncology Department: Medicine Format: Lecture Title: Clinical Issues in Hereditary Cancer Genetics Role: Lecturer Level: MSc program Time: 1.5 hour seminar Years: 2002-

Medical Genetics Unit 8 small group teaching in medical genetics Format: Small group interactive teaching Role: Lecturer Level: Medical Students Time: 5 small group sessions, 2 hours each

Genetic Counseling MSc course Department: Human Genetics Format: Lecture Title: Pathology in Cancer Genetics Role: Lecturer Level: MSc program Time: 1.5 hour seminar HGEN690 Hereditary Cancer Syndromes

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Department: Human Genetics Format: Lecture Title: Inherited Predisposition to Gastric cancer

DNA repair and pediatric cancer syndromes Role: Lecturer Level: MSc program Time: 2 hours

HGEN692 Human Genetics Department: Human Genetics Format: Lecture Title: Cancer Genetics I Role: Lecturer Level: MSc program Time: 3 hours HGEN692 Human Genetics Department: Human Genetics Format: Lecture Title: Cancer Genetics II Role: Lecturer Level: MSc program Time: 3 hours

BIOL370 Human Genetics Applied Department: Biology Format: Lecture Title: An introduction to Cancer Genetics Role: Lecturer Level: Undergraduate Time: 2 hours

INVITED LECTURES, TALKS, PRESENTATIONS

William Foulkes

January 17th, 2008 Title: The role of medical genetic services in the management of pediatric cancer patients and their families Joint meeting of the Departments of Medical Genetics and Pediatric Hematology/Oncology Montreal Children’s Hospital

March 13th 2008 Title: From the bedside to the bench and back again: short stories that end up as novels Breakthrough Breast Cancer Research Centre Seminar London, UK

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April 1st, 2008 Title: It is a short walk from the clinic to the laboratory, but sometimes you get lost on the way MUHC Urology seminar MUHC

April 10th, 2008 Title: From the bedside to the bench and back again: translating cancer genetics 1st Annual Canadian Human Genetics Conference Manoir St-Sauveur, St-Sauveur, Qc April 25-27, 2008

Title: Prevention/risk factors: Non-modifiable factors and hereditary breast cancer (Chair)

CBCRA Reasons for Hope Fifth Scientific Conference Vancouver, British Columbia May 12th, 2008 Title: Improving breast cancer mortality: have genetic markers helped? The 2008 CLIMOA Annual Scientific Meeting Sofitel Montreal, Montreal, Qc

June 7th, 2008 Title: Hereditary breast cancer: what is it, and why is it important? 5th World Conference on Breast Cancer Winnipeg, Manitoba

September 26th 2008 Title: Hereditary Ovarian Cancer- all you need to know Montreal General Hospital, Radiation Oncology MUHC

September 29th 2008 Title: From the bedside to the bench and back again University of Michigan Ann Arbor, MI, USA September 30th 2008 Title: Inherited susceptibility to common cancers University of Michigan

Ann Arbor, MI, USA

October 17th 2008 Title: Cancer Genetics Montreal Children’s Hospital MUHC

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November 11th-15th 2008 Title: 58th Annual Meeting of the American Society of Human Genetics Pennsylvania Convention Center Pennsylvania, Philadelphia November 20th 2008

Title: Clinically relevant biology of hereditary breast cancer 7th Amazon Project, Scientific Conference, Time across research and treatment of breast cancer: From memory to death and backwards Palermo, Italy

December 4th 2008 Title: Cowden syndrome Montreal General Hospital, Endocrinology Rounds MUHC

December 10th 2008

Title: Size, nodal status and survival in basal like breast cancer 2008 Triple Negative Breast Cancer Symposium Grand Hyatt San Antonio, Texas

Patricia Tonin

March 26th 2008 Title: Integrating genomic, gene expression and functional complementation strategies

to identify chromosome 3p genes implicated in ovarian cancer Samuel Lunenfield Research Institute Toronto, Ontario March 31st 2008 Title: The identification of chromosome 3 genes important in ovarian cancer through integration of genomic, gene expression and functional complementation strategies. Centre for Cancer Therapeutics, Ottawa Health Research Institute Ottawa, Ontario May 3rd 2008 Title: Genetics of Hereditary Ovarian Cancer The 4th Canadian Conference on Ovarian Cancer Research Montreal, Qc

Marc Tischkowitz

February 18th 2008 Title: Colorectal Cancer – who should be referred? JGH CRC rounds

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February 21st 2008 Title: Genetic screening for breast cancer Jewish General Hospital Surgical Rounds

February 25th 2008 Title: Familial Mediterranean Fever Jewish General Hospital Medical Rounds

May 8th 2008 Title: What has Fanconi Anemia taught us about breast cancer? CIHR Strategic Training Program, Winnipeg

September 10th 2008 Title: A primer on General and Cancer Genetics- useful tips for health professionals working in the community Purvinituq hospital, Purvinituq, Nunavik

Raquel Aloyz April 25-27th 2008 Title: Effect of kinase inhibitors in the growth of BRCA1-related breast cancer cells. CBCRA Reasons for Hope scientific conference

Vancouver, British Columbia June 25-28th 2008 Title: Disruption ff Brca2-Rad51Complex In Breast Cancer Cells. Era of Hope Meeting, The USA Department of Defence (DOD) Breast Cancer Research Program (BCRP). Baltimore Convention Center Baltimore, Maryland

October 1-2nd 2008 Title: New Therapies in CLL 4th Canadian CLL Meeting Inn at the Forks Winnipeg, Manitoba,

Ala-Eddin Al Moustafa

November 25th 2008 Title: High-Risk HPV Infection & Potential Therapies in Human Cancer Faculty of Pharmacy Aleppo University, Aleppo, Syria October 30th to November 2nd 2008 Title: High-Risk HPV/Gene Interactions In Human Carcinomas International Gynecologic Cancers Forum Wuxi No. 4 people’s Hospital, Wuxi, China

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July 28th 2008 Title: High-Risk HPV/Oncogene Interactions in Human Carcinomas The fourth affiliated hospital of Soochow university, Wuxi, China

July 25th 2008 Title: High-Risk HPV/Oncogene Interactions in Human Carcinomas Cancer Centre/Daping Hospital, Chongqing, China May 4-7th 2008 Title: ErbB2 and High-Risk HPV Interaction in Breast Tumorigenesis First International Medical Conference of the Aleppo University Aleppo, Syria

RESEARCH GRANTS

Acitve

Agency: CGCF Project: Correcting splicing in the mismatch repair gene PMS2 as a model for

therapy of genetic diseases Investigator: WD Foulkes Type: Operating Amount: 69,610 total Duration: 2009-2010

Agency: US Department of Defense Project: Exploring the pathogenic and therapeutic implications of

aberrant splicing in breast cancer Investigator: WD Foulkes, J Zhu Type: Synergistic Award Amount: US 333,387 WDF’s portion Duration: 2008-2010

Agency: Cancer Research Society, Inc

Project: Deletion analysis of BRCA1 and BRCA2 loci in selected high risk breast and/or ovarian cancer families of French Canadian descent

Investigator: PN Tonin Type: Operating Amount: $60,000/annum Duration: 2008 – 2010

Comment: Successful renewal of CRS grant “Contribution of TP53 and novel suspected cancer susceptibility genes in high risk breast and/or ovarian cancer families of French Canadian descent.”

Agency: Susan G Komen for the cure Project: Systematic Characterization of Dasatinib Sensitivity and Resistance in Breast Cancer Cells: Rationale for Patient Selection and Treatment Design Investigator: J Zhu, WD Foulkes

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Type: Operating Amount: US 192,000 WDF’s portion Duration: 2008-2011 Agency: Terry Fox Research Institute (Montreal Node) Project: A robust clinico-molecular platform to support the care of ovarian cancer patients Investigator: PN Tonin (Team Leader), W. Gotlieb, A. Kousik, A-M Mes- Masson, DP Provencher Type: Group Amount: $98,000 [for Year 1 – renewed every year to 3 years] Duration: 2008-2009 Agency: Cancer Research Society, Inc. Project: A model for modulating genetic and epigenetic events that influence the metastatic potential of ovarian cancer. Investigator: PN Tonin and A-M Mes-Masson (Co-PIs) Collaborators: M Chevrette, D Provencher Type: Strategic Grant Amount: $150,000/annum Duration: 2007 – 2009 Agency: Canadian Institutes of Health Research Project: An integrated functional and genomics approach at elucidating the chromosome 3 genes important in ovarian cancer. Investigator: Tonin PN Type: Operating Amount: $98, 517 per annum Duration: 2006 - 2009 Agency: Canadian Institutes of Health Research Project: Selection and validation of target genes implicated in the clinical and biological features of ovarian cancer Investigators: A-M Mes-Masson (PI), PN Tonin, D Provencher Type: Operating Amount: $150,000/annum Duration: 2008– 2013 Agency: Quebec Breast Cancer Foundation Project: The Discovery of Novel Tumor Suppressor Genes in Breast Cancer Investigators: M Basik (PI), S Mader, C Rancout, PN Tonin Type: Group-operating Amount: $1,499,128 [Total] Duration: 2004– 2007 [Extended to June 2008] Agency: Cancer Research Society, Inc

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Project: Contribution of TP53 and novel suspected cancer susceptibility genes in high risk breast and/or ovarian cancer families of French Canadian descent. Investigator: Tonin PN Type: Operating Amount: $60,000 per annum Duration: 2006 - 2008 Agency: Canadian Breast Cancer Research Alliance Project: Toward the biological treatment of BRCA1-related breast cancer: EGF, EGFR and tyrosine kinase inhibitors Investigator: Foulkes WD (PI), Bismar T, Aloyz R, Ghadirian P Type: Operating Amount: $413,834 total Duration: 2006 - 2009 Agency: Rethink Breast Cancer Project: Characterizing the role of Fanconi Anemia and Bloom Syndrome

genes in sporadic and hereditary cancer Investigator: Tischkowitz MD Type: Career Development Amount: $70,000 total Duration: 2006 - 2008 Agency: FRSQ Investigator: Tischkowitz MD Type: Chercheur-bousier clinicien Junior 1 Duration: 2007 - 2011 Agency: Susan G. Komen for the Cure Project: PALB2 - A new hereditary cancer gene: implications for treatment Investigator: Tischkowitz MD Type: Career Catalyst Research Amount: $290,000 total awarded March 2008 Agency: Susan G Komen Breast Cancer Foundation Project: The three-dimensional telomeric signature(s) of DCIS Investigator: Mai S (PI), Foulkes WD, Watson P Type: Operating Amount: US $249,000 total Duration: 2006 - 2009 Agency: Canada Foundation for Innovation Title of grant: Characterizing the role of Fanconi Anaemia and Bloom Syndrome genes

in sporadic and hereditary cancer Investigator: Tischkowitz MD Type: Laboratory Infrastructure

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Amount: CDN $103,795 awarded in March 2006 Agency: Cancer Research Society Title of grant: A model for modulating genetic and epigenetic events that influence the

metastatic potential of ovarian cancer. Investigators: Tonin PN (PI), Mes-Masson A-M, Chevrette M, Provencher D Type: Strategic Grant Amount: CDN$ 150,000 per annum Duration: 2007 - 2009 Comment: Successful renewal of CRS-Strategic Grant “A model for modulating

genetic and epigenetic events that influence the metastatic potential of ovarian cancer.”

Agency: Canadian Institutes of Health Research Title of grant: Selection and validation of target genes implicated in the clinical and

biological features of ovarian cancer Investigators: Mes-Masson A-M (PI), Tonin PN, Provencher D Type: Operating Amount: CDN$ 135,000 per annum Duration: 2005 - 2008 Comment: Successful renewal of CIHR grant “Selection and validation of

target genes implicated in the clinical and biological features of ovarian cancer”

Agency: Canadian Breast Cancer Research Alliance Title of Grant: BRCA1, CDC4, Cyclin E, and Chromosomal Instability in Breast

Cancer Investigators: Foulkes WD (PI), Mai S, Nielsen T Type: Operating Amount: CDN$ 430,000 total Duration: 2005 -2008 [Extended until June 2009] Agency: Canadian Institute of Health Research Title of grant: CIHR team grant in HPV infection and associated diseases Investigator: Franco E (PI), Al Moustafa A-E Type : Team Grant Amount: CDN$ 508,218 per annum Duration: 2007 – 2012 Agency: Canadian Breast Cancer Research Initiative Title of Grant: Risk factor analysis of hereditary breast and ovarian cancer Investigators: Narod S (PI), Foulkes WD Type: Operating Amount: CDN$ 1,250,000 total Duration: 2004 - 2009 Agency: Quebec Breast Cancer Foundation

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Title of the grant: The Discovery of Novel Tumor Suppressor Genes in Breast Cancer Investigators: Basik M (PI), Mader S, Rancourt C, Tonin PN Type: Group-operating Amount: CDN$1,499,128 total Duration: 2004 - 2008 Agency; NIH Title of Grant: The Genetic of Prostate Cancer: The ICPCG Study Investigators: Isaacs WB (PI), Foulkes WD, Epstein J, Partin A, Easton D, Eeles R,

Maehle L, Giles GG, Hopper J, Whittemore AS, Halpern J, Hsieh CL, Cussenot O, Cancel G, Jarvik G, Badzioch M, Stanford J, Ostrander E, Schaid D, Thibodeau S, Gronberg H, Cooney K, Lange E, Schleutker J, Vogel Wm Cannon-Albright L, Camp NJ, Xu J, Meyers D,

Type: Operating Amount: USD$ 2,097,089 total Duration: 2002 - 2006, [Extended until 2009]

Agency: Canadian Institute of Health Research (CIHR) Title of grant: Experimental and clinical cancer research from gene function to

functional analysis Investigators: Tremblay M, Banton PE, Giguere V, Gros P, Muller WJ, Park M, Shore

G, Sonenberg N, Tonin PN Type: Strategic Training Program Grants Amount: $1,680,000 Duration: 2002 - 2008 Agency: Fonds de la Recherche en Santé du Québec: Reseau cancerologie Title of grant: Banque de tissues et de données pour le cancer du sein et du l’ovaire Investigators: Alpert L, Bachvarov D, Basik M, Batist G, Brisson J, Foulkes WD,

Ghadirian P, Hudson T, Mes-Masson A-M, Park M, Poirier G, Provencher D, Rancourt C, Tonin PN

Type: Infrastructure - Group Amount: CDN $900,000 per annum Duration: 2007 - 2012. Comment: Successful renewal of FRSQ Cancer Reseau/Network grant “Banque de

tissues et de données pour le cancer du sein et du l’ovaire” Agency: Canadian Institute of Health Research (CIHR) Title of grant: Mechanisms of dasatinib toxicity and sensitization of standard

therapy in chronic lymphocytic leukemia Investigators: Aloyz R Type: Operating Amount: $62,800 per year Duration: 2006 - 2009 Agency: NIH

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Title of grant: MRI-based tumor targeting enhancement with magnetotactic bacterial carriers

Amount: $405,000 per year Investigators: Martel S (PI), Aloyz R Type: Operating Duration: 2007 - 2010 Agency: Luitpold Pharmaceuticals Title of grant: Evaluation of DNA-PK inhibitors in malignant human cells Investigators: Aloyz R, Panasci L Type: N/A Amount: $110,740 per year Duration: 2007 - 2010

Agency: Jewish General Hospital Foundation Title of grant: Effect of Xrcc3, a DNA repair associated gene, on cell adhesion and

motility Investigators: Aloyz A, Aloui-Jamali M Type : Weekend to End Breast Cancer Amount : $35,000

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annual report january 2008 to december 2008 program in cancer

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