Molecular diagnostics of familial cancer-prone diseases
Prof. Dr. C. R. Bartram, MD
Dr. Christian Sutter, PhD
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.
Farnoosh Fathali Zadeh, biotechnologist
Jochen Meyer, technician
Verena Wahl, technician
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)
1. Frank B, Hemminki K, Meindl A, Wappenschmidt B, Sutter C, Kiechle M, Bugert P, Schmutzler RK, Bartram CR, Burwinkel B.: BRIP1 (BACH1) variants and familial breast cancer risk: a case-control study. BMC Cancer. 2007 May 15;7:83.
2. Frank B, Bermejo JL, Hemminki K, Sutter C, Wappenschmidt B, Meindl A, Kiechle M, Bugert P, Schmutzler RK, Bartram CR, Burwinkel B. Copy number variant in the candidate tumor suppressor gene MTUS1 and familial breast cancer risk. Carcinogenesis. 2007 Feb 13; (Epub ahead of print)
3. Vaclavicek A, Bermejo JL, Wappenschmidt B, Meindl A, Sutter C, Schmutzler RK, Kiechle M, Bugert P, Burwinkel B, Bartram CR, Hemminki K, Försti A.:Genetic variation in the major mitotic checkpoint genes does not affect familial breast cancer risk. Breast Cancer Res Treat. 2007 Feb 1; [Epub ahead of print]
4. Wirtenberger M, Schmutzhard J, Hemminki K, Meindl A, Sutter C, Schmutzler RK, Wappenschmidt B, Kiechle M, Arnold N, Weber BH, Niederacher D, Bartram CR, Burwinkel B.: The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer. Carcinogenesis. 2007 Feb;28(2):423-6. Epub 2006 Sep 6.
5. Tchatchou S, Wirtenberger M, Hemminki K, Sutter C, Meindl A, Wappenschmidt B, Kiechle M, Bugert P, Schmutzler RK, Bartram CR, Burwinkel B.: Aurora kinases A and B and familial breast cancer risk. Cancer Lett. 2007 Mar 18;247(2):266-72. Epub 2006 Jun 9.
6. Burwinkel B, Shanmugam KS, Hemminki K, Meindl A, Schmutzler RK, Sutter C, Wappenschmidt B, Kiechle M, Bartram CR, Frank B.: Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study.: BMC Cancer. 2006 Nov 17;6:268.