1. New genetic cancer tests
within gynecology
Patrick Willems
GENDIA
Antwerp, Belgium

2. or Disclosure CEO and shareholder of GENDIA
(private lab offering genetic tests)
NO financial relationship with research bodies, medical
or pharmaceutical companies, hospitals or government or

3. 2. SOMATIC MUTATIONS IN CANCER
New genetic tests
1. GERMLINE MUTATIONS
NIPT
STID
WES / WGS
CANCER RISK
2. SOMATIC MUTATIONS IN CANCER
DNA profiling of tumors
CT-DNA (liquid biopsy)

4. New genetic tests
In procreation
NIPT and STID

5. NIPT www.DOWNsyndromeNIPT.info NON – INVASIVE PRENATAL TESTING
Testing of cff DNA (cell free fetal DNA)
from maternal blood during pregnancy
for trisomy 21, 18 and 13, and fetal sex

6. NIPT NIPT currently is most common genetic test
The most common genetic test :
Approximately 1 million NIPTs per year worldwide
Future Market value : 4 billion US / year
(price : 300 – 500 Euro per test)

7. STID SCREENING TEST for INHERITED DISEASE
With testing of common recessive diseases
from parental blood before or during pregnancy
If both parents are carrier of the same disease
the fetus has a 25 % risk of being affected
and prenatal testing (CVS/AC) can be offered

8. STID for Recessive disorders
Gene
Frequency
Cystic Fibrosis
CFTR
1/3000
Spinal muscular atrophy
SMN1
1/5000
Deafness
GJB2
1/2000
Fragile X
FMR1
Thalassemia
HBB
1/3000 (1/300)
Many metabolic disorders
100 genes
1/200

9. New genetic tests for cancer
CANCER RISK test
DNA profiling test
CT-DNA test

10. Genetics of cancer Majority of cancers are caused by somatic mutations
only occuring in the tumor
Minority of cancers is inherited due to germline mutations
occuring in all cells (also germline) :
Ovarian Cancer : 15 %
Breast Cancer : %
Colon cancer : %
Prostate cancer : low
Lung cancer : very low

11. CANCER RISK test in BOC Germline DNA testing
Classical BOC testing
BRCA1/2 test
2 genes in patients
Single mutations in family members
Selected families
Patients affected with BOC
Young patients
Multiplex families with multiple affected members
Ovarian Ca

12. Germline DNA testing in BOC
BOC testing of BRCA1/2 only identifies 50 % of mutations
BOC testing of BRCA1/2 misses therapeutic targets
Selected family testing only identifies 50 % of mutations

13. Germline DNA testing in BOC
BOC testing of BRCA1/2 only identifies 50 % of mutations
BOC testing of BRCA1/2 misses therapeutic targets
Selected family testing only identifies 50 % of mutations

14. Germline mutations in BOC
Breast cancer : 10 % is inherited
BRCA1 and BRCA2 mutations : 5 %
CHEK2, ATM, TP53, PALB2: 3-5 %
Other mutations : ?
Ovarian cancer : 15 % is inherited
BRCA1 and BRCA2 mutations : 10 %
HNPCC mutations : 1-2 %
CHEK2,ATM,TP53,PALB2,BARD1,BRIP1,CDH1,EPCAM,MLH1,
MSH2, MSH6,NBN,PMS2,PTEN,RAD51C,RAD51D,STK11
BRCA1/2

15. Germline DNA testing in BOC
BOC testing of BRCA1/2 only identifies 50 % of mutations
BOC testing of BRCA1/2 misses therapeutic targets
Selected family testing only identifies 50 % of mutations

16. Germline DNA testing in BOC
PARP inhibitors for tumors with deficient DNA repair :
Deficient DNA repair due to mutations in BRCA1/2
Deficient DNA repair due to mutations in other genes : BARD1, BRIP1, PALB2, ATM, CHEK2,
PTEN, RAD51C, RAD51D, NBN, TP53,
EPCAM, MLH1, MSH2, MSH6, PMS2 ,

17. Germline DNA testing in BOC
BOC testing of BRCA1/2 only identifies 50 % of mutations
BOC testing of BRCA1/2 misses therapeutic targets
Selected family testing only identifies 50 % of mutations

18. CGC-based genetic screening
CGC (Clinical Genetics Center) Criteria :
Patients affected with BOC
Young patients
Multiplex families
Ovarian Ca

19. BOC testing for all women
50 % of women with BOC mutation
do not fulfill CGC criteria
Mary-Claire King advocates
genetic screening of all adult women
(JAMA vol 312, Sept 2014)

20. Breast cancer testing BRCA1/2 in selected patients with high risk
PREVIOUSLY :
BRCA1/2 in selected patients with high risk
CURRENTLY :
Screening of ALL BOC genes in ALL women

21. Cancer risk test Sequencing of 30 cancer genes :
19 genes involved in BOC :
BRCA1, BRCA2, ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM,MLH1, MSH2,
MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53 +
11 genes involved in colon, uterine, pancreas, and skin cancer :
APC, BAP1, BMPR1A, CDKN2A, CDK4, GREM1,
MITF, MUTYH, POLD1, POLE, and SMAD4

22. What if I have a mutation ?
Children have 50 % risk of inheriting the mutation
If already BOC, personalised treatment
eg with herceptin, PARP inhibitors
If unaffected : increased risk for BOC
Increased surveillance (MRI, Mammography, CA125, abdominal echography, CT-DNA liquid biopsy)
Profylactic surgery : 51% bilateral mastectomy; 64% oophorectomy (Meijers H. The Lancet, june 2000)

24. 2. SOMATIC MUTATIONS IN CANCER
New genetic tests
1. GERMLINE MUTATIONS
NIPT
STID
WES / WGS
CANCER RISK
2. SOMATIC MUTATIONS IN CANCER
DNA profiling of tumors
CT-DNA (liquid biopsy)

25. DNA profiling of BOC tissue
CURRENT TESTING of BOC tissue :
Estrogen receptor (ER) : tamoxifen (anti-E), anastrozole (anti-Aromatase)
Progesteron receptor (PR) : mifepristone
HER2 : Herceptin
FUTURE TESTING of BOC tissue :
DNA repair genes : PARP inhibitors (Olaparib, Iniparib, Veliparib)
Microsatellite instability (MSI): immunotherapy
RNA signature to determine thr need of chemo
Driver genes : targeted therapy with designer molecules

26. Frequency of oncogenic mutations in different cancers
GENE
Lung
Colon
Breast
Ovary
Melanoma
Prostate
Pancreas
EGFR 30 50 3
TP53 34 45 23 46 12 14 36
KRAS 17 4 57
BRAF 1 11 7 2
PIK3CA 26 9
NRAS 18
CTNNB1 48 6
2-3
GNAS 16
FOXL2

27. Treatment of cancer Personalised treatment Surgery Radiation
Chemotherapy
Personalised treatment

28. Targeted treatment for cancer
Personalised targeted treatment inhibits
specific mutations that cause cancer
These mutations are patient-specific
Therapy is dependent upon the specific mutation
Mutations can be detected by molecular studies of :
. tumor material (biopsy) : FFPE, fresh or frozen
. blood (liquid biopsy)

29. in plasma of healthy individuals (Mandel and Métais,1948)
cell-free DNA testing
Cell-free DNA (cfDNA)
in plasma of healthy individuals (Mandel and Métais,1948)

30. cell-free DNA testing
Cell-free DNA (cfDNA) in plasma of healthy individuals (Mandel and Métais,1948)
cffDNA (NIPT) : Cell-free DNA from the fetus in the maternal circulation
A proportion of cfDNA in pregnant women is fetus-derived (cffDNA) : Lo et al. (1997)
Non-Invasive Prenatal testing (NIPT) : 2012 : start
2015 : > 1 million tests
  Market : 4 billion USD
ctDNA (liquid biopsy) Cell-free DNA from the cancer cells in the circulation
Increased concentrations of cfDNA in the circulation of cancer patients : Leon et al. (1977)
A proportion of cfDNA is tumor-derived : Stroun et al. (1987)
Circulating tumor DNA (ctDNA) testing (liquid biopsy) : 2015 : start
  Market : 40 billion USD

31. CT DNA test screens Circulating Tumor DNA
from the cancer cells in blood (liquid biopsy)

32. CT-DNA test on liquid biopsy
GENE
PROTEIN
MUTATIONS
EGFR
Epidermal growth factor receptor 32
TP53
Tumor protein p53 9
KRAS
Kirsten rat sarcoma viral oncogene 18
BRAF
Braf murine sarcoma viral oncogene 6
PIK3CA
Phosphatidylinositol 3-kinase, catalytic, alpha 14
NRAS
Neuroblastoma ras viral oncogene 10
CTNNB1
Catenin, beta-1 4
GNAS
Guanine nucleotide-binding protein, alpha 2
FOXL2
Forkhead transcription factor foxl2 1
1. DESCRIPTION : 96 mutations in 9 cancer genes
2. SAMPLE : blood in specific test kits with Streck tubes (GENDIA)
3. TURNAROUND TIME : 3 weeks
4. PRICE : Euro

33. Advantages liquid biopsies
No tissue biopsy needed
No FFPE fixation
Profiling the overall genotype of cancer
primary cancer
circulating cells
metastases
Better evaluation of :
reaction to therapy
development of resistance
Also screening of patients without tumor but high cancer risk

34. Indications for CT DNA testing (liquid biopsy)
Follow up of patients with cancer during treatment
Screening of individuals at high risk for cancer
BRCA, HNPCC carriers
History of cancer
Family history of cancer
In the future : annual screening of all adults

35. From patient testing towards population screening
Form testing of 1 gene in 1 % of the population
suspected of a genetic disorder to :
Whole genome testing (WGS) of the whole population
to identify germline mutations
2. Annual screening for cancer DNA by liquid biopsy
to identify somatic mutations