Kliniken & Institute … Institute Institute of Human… Research Department of Human… Molecular Diagnostics…

Molecular Diagnostics for Familial Cancer

Project Management

[Translate to English:] Portrait von Prof. Dr. med. Christian Schaaf
Prof. Dr. med. Christian Schaaf

Geschäftsführender Direktor des Instituts, Direktor der Abteilung Humangenetik


+49 6221 56-5151
+49 6221 56-5155

Laboratory Management

Portrait von Dr. rer. nat. Christian Sutter
Dr. rer. nat. Christian Sutter
Focus

Hereditary tumor diseases, Sanger sequencing


+49 6221 56-39567
+49 6221 56-5091

Breast Cancer is the most common tumor occuring in women. Improved cancer cure is not only the result of new therapeutic approaches, but also the result of improved options of early detection of neoplasia. In Germany every year 40.000 new cases of breast cancer are diagnosed. On average one out of ten women will suffer from breast cancer during lifetime. Approximately 5% of breast tumors occur on a hereditary basis, up to 25% of  causative genetic alterations are detected in the high-penetrance genes  BRCA1 und BRCA2 while the remainder may be explaned by combinations of variants in low-penetrance susceptibility genes.

Topic of current research is the identification of low-penetrance susceptibility genes in BRCA1/ BRCA2 mutation-negative breast cancer families as well as identification of genes modifying breast cancer risk in families carrying a BRCA1/ BRCA2 germline mutation.

1. CCPRB (Cancer Control using Population-based Registries and Biobanks)

Work Package JER-2 (Genetic Epidemiology of Cancer, EU research program), until 31.05.09.

Based on molecular epidemiologic approaches in a collaborative research program together with Prof. Hemminki and Prof. Burwinkel, German Cancer Research Center, Heidelberg, it is planned to identify genes associated with familial breast cancer. This approach is carried out on the basis of thoroughly characterized cohorts of patients' samples where BRCA1/ BRCA2 mutations have been excluded (high and low risk breast cancer families).

Respective DNA samples are collected in a biobank and provided by the Institute of Human Genetics for the identification of low-penetrance genes associated with breast cancer risk.

So far, numerous genetic alterations in genes associated with breast cancer risk could be identified and published.

2. Genome-wide association study regarding familial breast cancer (German Cancer Aid)

Based on more than 1000 thoroughly documented cohorts of high-risk breast cancer families where causative BRCA1/ BRCA2 mutations had been excluded it is planned to identify breast cancer predisposing genes or gene variants.

This approach will be carried out by linkage disequilibrium studies on patients' samples using 500K Affymetrix gene chips compared to age-adjusted patient controls. In a second step detailed mapping using SNP markers will be carried out to identify putative candidate genes. Respective DNA samples are collected in a biobank and provided by the Institute of Human Genetics.

3. International collaboration research program of the German Consortium for Familial Breast Cancer with theCIMBA Consortium (Consortium of Investigators of Modifiers of BRCA1/2) to identify genetic variants modifying breast cancer risk

In this international study (Coordinator for Germany: Prof. R.K. Schmutzler, Cologne) patients/ families with already identified causative germline mutation for familial breast and ovarian cancer are investigated regarding additional genetic alterations which might influence breast cancer risk.

This approach is carried out on cohorts of thoroughly molecularly characterized samples which are provided by the Institute of Human Genetics to the CIMBA collaborating program for association studies.

Team members:

Farnoosh Fathali Zadeh, biotechnologist

Former members:

Jochen Meyer, technician
Verena Wahl, technician

Collaborations:

Prof. Dr. Kari Hemminki, DKFZ Heidelberg
Prof. Dr. Barbara Burwinkel, Women's Hospital, University of Heidelberg
Prof. Dr. Rita Schmutzler
Prof. Dr. Alfons Meindl
and the German Consortium for Hereditary Breast- and Ovarian Cancer (GC-HBOC)

Selected Publications

1) Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, Eccles D, Evans DG, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Stratton MR, Rahman N, Jacobs K, Prentice R, Anderson GL, Rajkovic A, Curb JD, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver WR, Bojesen S, Nordestgaard BG, Flyger H, Dörk T, Schürmann P, Hillemanns P, Karstens JH, Bogdanova NV, Antonenkova NN, Zalutsky IV, Bermisheva M, Fedorova S, Khusnutdinova E; SEARCH, Kang D, Yoo KY, Noh DY, Ahn SH, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Garcia-Closas M, Lissowska J, Brinton L, Peplonska B, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Hopper JL, Southey MC, Smith L, Spurdle AB, Schmidt MK, Broeks A, van Hien RR, Cornelissen S, Milne RL, Ribas G, González-Neira A, Benitez J, Schmutzler RK, Burwinkel B, Bartram CR, Meindl A, Brauch H, Justenhoven C, Hamann U; GENICA Consortium, Chang-Claude J, Hein R, Wang-Gohrke S, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kataja V, Olson JE, Wang X, Fredericksen Z, Giles GG, Severi G, Baglietto L, English DR, Hankinson SE, Cox DG, Kraft P, Vatten LJ, Hveem K, Kumle M, Sigurdson A, Doody M, Bhatti P, Alexander BH, Hooning MJ, van den Ouweland AM, Oldenburg RA, Schutte M, Hall P, Czene K, Liu J, Li Y, Cox A, Elliott G, Brock I, Reed MW, Shen CY, Yu JC, Hsu GC, Chen ST, Anton-Culver H, Ziogas A, Andrulis IL, Knight JA; kConFab; Australian Ovarian Cancer Study Group, Beesley J, Goode EL, Couch F, Chenevix-Trench G, Hoover RN, Ponder BA, Hunter DJ, Pharoah PD, Dunning AM, Chanock SJ, Easton DF.: Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

Nat Genet. 2009 May;41(5):585-90. Epub 2009 Mar 29.

2) Milne RL, Benítez J, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Arias JI, Zamora MP, Burwinkel B, Bartram CR, Meindl A, Schmutzler RK, Cox A, Brock I, Elliott G, Reed MW, Southey MC, Smith L, Spurdle AB, Hopper JL, Couch FJ, Olson JE, Wang X, Fredericksen Z, Schürmann P, Bremer M, Hillemanns P, Dörk T, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Hall P, Czene K, Liu J, Li Y, Ahmed S, Dunning AM, Maranian M, Pharoah PD, Chenevix-Trench G, Beesley J; kConFab Investigators; AOCS Group, Bogdanova NV, Antonenkova NN, Zalutsky IV, Anton-Culver H, Ziogas A, Brauch H, Justenhoven C, Ko YD, Haas S, Fasching PA, Strick R, Ekici AB, Beckmann MW, Giles GG, Severi G, Baglietto L, English DR, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Turnbull C, Hines S, Renwick A, Rahman N, Nordestgaard BG, Bojesen SE, Flyger H, Kang D, Yoo KY, Noh DY, Mannermaa A, Kataja V, Kosma VM, García-Closas M, Chanock S, Lissowska J, Brinton LA, Chang-Claude J, Wang-Gohrke S, Shen CY, Wang HC, Yu JC, Chen ST, Bermisheva M, Nikolaeva T, Khusnutdinova E, Humphreys MK, Morrison J, Platte R, Easton DF; Breast Cancer Association Consortium.: Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042.

J Natl Cancer Inst. 2009 Jul 15;101(14):1012-8. Epub 2009 Jun 30.

3) Gaudet MM, Milne RL, Cox A, Camp NJ, Goode EL, Humphreys MK, Dunning AM, Morrison J, Giles GG, Severi G, Baglietto L, English DR, Couch FJ, Olson JE, Wang X, Chang-Claude J, Flesch-Janys D, Abbas S, Salazar R, Mannermaa A, Kataja V, Kosma VM, Lindblom A, Margolin S, Heikkinen T, Kämpjärvi K, Aaltonen K, Nevanlinna H, Bogdanova N, Coinac I, Schürmann P, Dörk T, Bartram CR, Schmutzler RK, Tchatchou S, Burwinkel B, Brauch H, Torres D, Hamann U, Justenhoven C, Ribas G, Arias JI, Benitez J, Bojesen SE, Nordestgaard BG, Flyger HL, Peto J, Fletcher O, Johnson N, Dos Santos Silva I, Fasching PA, Beckmann MW, Strick R, Ekici AB, Broeks A, Schmidt MK, van Leeuwen FE, Van't Veer LJ, Southey MC, Hopper JL, Apicella C, Haiman CA, Henderson BE, Le Marchand L, Kolonel LN, Kristensen V, Grenaker Alnaes G, Hunter DJ, Kraft P, Cox DG, Hankinson SE, Seynaeve C, Vreeswijk MP, Tollenaar RA, Devilee P, Chanock S, Lissowska J, Brinton L, Peplonska B, Czene K, Hall P, Li Y, Liu J, Balasubramanian S, Rafii S, Reed MW, Pooley KA, Conroy D, Baynes C, Kang D, Yoo KY, Noh DY, Ahn SH, Shen CY, Wang HC, Yu JC, Wu PE, Anton-Culver H, Ziogoas A, Egan K, Newcomb P, Titus-Ernstoff L, Trentham Dietz A, Sigurdson AJ, Alexander BH, Bhatti P, Allen-Brady K, Cannon-Albright LA, Wong J; Australian Ovarian Cancer Study Group, Chenevix-Trench G, Spurdle AB, Beesley J, Pharoah PD, Easton DF, Garcia-Closas M; Breast Cancer Association Consortium.: Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1610-6.

4) Tchatchou S, Jung A, Hemminki K, Sutter C, Wappenschmidt B, Bugert P, Weber BH, Niederacher D, Arnold N, Varon-Mateeva R, Ditsch N, Meindl A, Schmutzler RK, Bartram CR, Burwinkel B.: A variant affecting a putative miRNA target site in estrogen receptor (ESR) 1 is associated with breast cancer risk in premenopausal women.

Carcinogenesis. 2009 Jan;30(1):59-64. Epub 2008 Nov 20.

5) Frank B, Wiestler M, Kropp S, Hemminki K, Spurdle AB, Sutter C, Wappenschmidt B, Chen X, Beesley J, Hopper JL; Australian Breast Cancer Family Study Investigators,, Meindl A, Kiechle M, Slanger T, Bugert P, Schmutzler RK, Bartram CR, Flesch-Janys D, Mutschelknauss E, Ashton K, Salazar R, Webb E, Hamann U, Brauch H, Justenhoven C, Ko YD, Brüning T, Silva Idos S, Johnson N, Pharoah PP, Dunning AM, Pooley KA, Chang-Claude J, Easton DF, Peto J, Houlston R; Gene Environment Interaction and Breast Cancer in Germany Group, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Investigators, Australian Ovarian Cancer Study Management Group, Chenevix-Trench G, Fletcher O, Burwinkel B.: Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis.

J Natl Cancer Inst. 2008 Mar 19;100(6):437-42. Epub 2008 Mar 11

6) Yang R, Frank B, Hemminki K, Bartram CR, Wappenschmidt B, Sutter C, Kiechle M, Bugert P, Schmutzler RK, Arnold N, Weber BH, Niederacher D, Meindl A, Burwinkel B.: SNPs in ultraconserved elements and familial breast cancer risk.

Carcinogenesis. 2008 Feb;29(2):351-5. Epub 2008 Jan 3.

7) Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kämpjärvi K, Nevanlinna H, Simard J, Beesley J, Chen X; Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Neuhausen SL, Rebbeck TR, Wagner T, Lynch HT, Isaacs C, Weitzel J, Ganz PA, Daly MB, Tomlinson G, Olopade OI, Blum JL, Couch FJ, Peterlongo P, Manoukian S, Barile M, Radice P, Szabo CI, Pereira LH, Greene MH, Rennert G, Lejbkowicz F, Barnett-Griness O, Andrulis IL, Ozcelik H; OCGN, Gerdes AM, Caligo MA, Laitman Y, Kaufman B, Milgrom R, Friedman E; Swedish BRCA1 and BRCA2 study collaborators, Domchek SM, Nathanson KL, Osorio A, Llort G, Milne RL, Benítez J, Hamann U, Hogervorst FB, Manders P, Ligtenberg MJ, van den Ouweland AM; DNA-HEBON collaborators, Peock S, Cook M, Platte R, Evans DG, Eeles R, Pichert G, Chu C, Eccles D, Davidson R, Douglas F; EMBRACE, Godwin AK, Barjhoux L, Mazoyer S, Sobol H, Bourdon V, Eisinger F, Chompret A, Capoulade C, Bressac-de Paillerets B, Lenoir GM, Gauthier-Villars M, Houdayer C, Stoppa-Lyonnet D; GEMO, Chenevix-Trench G, Easton DF; CIMBA.: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Am J Hum Genet. 2008 Apr;82(4):937-48. Epub 2008 Mar 20.

EN