Erfelijke tumoren. P. Devilee Leids Universitair Medisch Centrum

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1 Erfelijke tumoren P. Devilee Leids Universitair Medisch Centrum

2 Waarom erfelijke tumoren herkennen? Erfelijke tumoren zijn anders Pathologie Klinisch beloop Respons op therapie Preventie bij gezonde gendragers Primair: profylaxis, chemopreventie Secundair: screening

3 Alles is genetisch! Genetisch determinisme Nature-nurture Individuele variatie: Vatbaarheid voor ziekte Respons op therapie

4 Aanwijzingen voor genen Families Tweelingen Algemene populatie Case-control studies

5 Het zit in de familie

6 Erfelijke tumor syndromen Zeldzame tumoren Frequent, duidelijk overervingspatroon Typerende familaire clusteringen Borst + Ovarium Darm + Endometrium

7 Genen versus omgeving Kanker incidentie gegevens van 44,788 tweelingparen uit Scandinavië Cancer Proportion of variance due to Genes Shared Env Non-Shared Env Breast Ovary Lung Colon Prostate Lichtenstein et al. (2000) NEJM 343:78.

8 Familiaire belasting bij borstkanker Aantal 1 e -graads verwanten met borstkanker 1 % onder gezonde controles % onder borstkanker patiënten Relatief risico (99% CI) Geen ( ) ( ) ( ) 3 of meer ( ) 1 Moeder, zus, dochter. Gegevens van Collaborative Group on Hormonal Factors in Breast Cancer (2001).

9 Familiair risico Cancer in proband Relative risk 95% CI for FDR Breast cancer Colon cancer Kidney cancer Laryngeal cancer Lung cancer Lymphocytic leukemia Melanoma Ovarian cancer Prostate cancer Testicular cancer Thyroid cancer Goldgar et al. (1994) J Natl Cancer Inst 86: 1600

10 Genetische verklaringen Mutaties in het DNA Zeldzaam Frequent Kanker risico s Hoog Laag Combinaties hiervan

11 Gen frequentie en risico high Rare, high risk, Mendelian disease Highly unusual for common disease Risk low Uncommon, moderate risk Common, low risk, population Allele frequency Manolio et al. Nature 461, (2009)

12 Monogenic disease Rare high risk variant Br69 Non-penetrant obligate carrier Br58 Br57 Br45 Br41 Br44 (Near-)perfect co-segregation with disease Easily detected by parametric linkage analysis Accounts for incomplete penetrance and phenocopies

13 Genen uit familie onderzoek Genetische koppeling en kandidaat gen-sequencing Families with Gene(s) Breast/Ovarian cancer BRCA1, BRCA2 Colon cancer APC, MLH1, MSH2 Kidney, brain VHL Thyroid PTEN Thyroid (MEN2) RET Retinoblastoma RB1 Li-Fraumeni Syndrome TP53 Neurofibromatosis NF1, NF2

14 Zeldzaam, maar hoge risico s Gen Frequentie Risico* tot 70 jr BRCA1 1 / % MLH1 1 / % RB1 1 / % * Het risico op de met dit gen geassocieerde vorm(en) van kanker

15 Het belang van een DNA diagnose Pre-symptomatische diagnostiek Primaire preventie Screening Voor patiënten Andere behandel-opties Intensievere follow-up

16 Bestraling & BRCA1/2 gendragerschap Hogere incidentie contralateraal mammacarcinoom na radiotherapie Hogere kans op primair mammacarcinoom bij RX-thorax Mammografie? Studies niet significant of negatief Broeks et al (2007); Andrieu et al (2006); Pijpe et al (2012)

17 BRCA1/2 & ovarium carcinoom Survival and response to cisplatin treatment Overall Survival Progression-free Survival Platinum-free Survival Yang, D. et al (2011) JAMA 306:1557

18 PARP remmers Poly ADPribose polymerase Fong et al. N Engl J Med Jul 9;361(2):

19 Mismatch repair & CRC therapie resistentie Goede prognose MMR-deficiente cellen zijn tolerant voor DNA-methylerende middelen (temozolomide) DNA-alkylerende middelen (busulfan) Platinum-drugs (cisplatin, carboplatin) Topoisomerase II remmers (etoposide, doxorubicin) Resistentie tegen 5FU adjuvante chemotherapie Buecher et al., 2013

20 Wie is genetisch belast? Percentage patiënten verklaard door bekende hoog-risico genen All cancer Familial Cancer Unknown polygenic predisposing genes Other known genes Environmental factors Familial genes Strong predisposing genes Unknown familial predisposition genes 2-3% 20-25%

21 Associatie studies

22 Manhattan plot GWAS with SNPs; Genome-wide significance: p < 5 x 10-8 Manolio (2010) N Eng J Med 363; 166

23 Frequent, maar lage risico s Eerste borstkanker SNPS als voorbeeld SNP (Gen) Frequentie %Het 1 Het.OR 2 rs (FGFR2) rs (TOX3) rs (MAP3K1) rs (8q24) rs (LSP1) heterozygote; 2 Odds ratio in heterozygotes vs common homozygotes Easton et al., 2007

24 Common SNPs & common cancers Cancer site Number of SNP Reference loci associated* Prostate 72 Eeles et al (2013) Colon 20 Dunlop et al (2012) Breast 67 Michailidou et al (2013) Lung 16 Chu et al (2014) *Independent signals at genome-wide significance (p<5x10-8 )

25 Het multifactoriële model Number of individuals Healthy controls cases Risk allele 1 Risk allele 2 Risk allele 3 Risk allele 4 Risk allele 5 Risk allele 6 Disease risk normal allele risk allele 25

26 All breast cancer SNPs (N = 33,381) (N = 33,673) 77 SNPs max 154 risk alleles Mavaddat et al, JNCI, in press

27 Interacties tussen SNPs?

28 A polygenic risk score (PRS) Under a polygenic multiplicative model 5% of women 5% of women For women in the highest 1% of the PRS, the estimated OR compared with women in the middle quintile was 3.36 (95%CI: , p=7.5x10-74 ) Mavaddat et al, JNCI, in press

29 Risk of developing breast cancer All Breast Cancers All Absolute Breast Cancers lifetime risk 0.35 >99% % 90-95% % 60-80% Absolute risk % 20-40% 10-20% 5-10% 1-5% <1% 80% of women Age (years) Mavaddat et al, JNCI, in press

30 PRS and family history Mavaddat et al, JNCI, in press

31 Colorectal cancer Case-control study (n=39,266) with 10 low risk SNPs Dunlop et al (2013) Gut;62:

32 Common SNPs are poor predictors of individual risk 10 risk SNPs (39,266 subjects) 10 SNPs plus age, family history status and gender (11,324 subjects) (sensitivity) (1-specificity) Dunlop et al (2013) Gut;62:

33 10-Year risk to develop breast cancer in the Netherlands 4.00% 3.50% Absolute risk 3.00% 2.50% 2.00% 1.50% Start mammographic screening 1.00% 0.50% 0.00% Age Data: Netherlands Cancer Registry,

34 Risk stratification 10 year risk year risk all breast All Breast cancers, Cancers by SNP profile >99% 95-99% 90-95% 80-90% 60-80% 40-60% OR = % 10-20% 5-10% 1-5% <1% Age (years) 20% of women reach threshold before age 40 Screening threshold 20-40% of women never reach threshold Mavaddat et al, JNCI, in press

35 Clinical Implications 17% of cases Clinical Guideline: Enhanced surveillance when lifetime risk >17% AUC of 77 SNPs = 0.62 Incorporate other risk factors Pop. Avg. Risk 8% of women

36 Common SNPs interact with high risk mutations BRCA2-risk modification by 7 common breast cancer SNPs 90% 50% Of all carriers Antoniou et al. (2010)

37 Gen frequentie en risico high Rare, high risk, Mendelian disease Highly unusual for common disease Risk low Uncommon, moderate risk Common, low risk, population Allele frequency Manolio et al. Nature 461, (2009)

38 Genetic architecture of breast cancer CDH1 TP53 BRCA1 10 BRCA2 STK11 Rela%ve Risk PTEN PALB2 CHEK2 ATM Allele frequency Risk SNPs

39 Fraction familial risk explained Cancer site Rare high risk and Common SNPs intermediate risk loci Prostate <5% 30% Colon 25% ~15% Breast 25% 30% Lung? 10%

40 Counseling familial cancer Current practice Aimed at identifying or excluding high risk Test affected individual In positive families: Carriers are given gene-specific risks Those testing negative are given population risk In negative families, family history determines risk Future practice A more holistic approach, aimed at establishing individual risk Anyone can be tested A wide range of risk levels can be found Some risk factors are modifiable

41 Samenvatting Erfelijkheid van kanker wordt bepaald door hoog- en laag-risico DNA variatie Hoog-risico variatie is zeldzaam, laagrisico variatie frequent DNA-diagnostiek voor hoog-risico variatie is klinisch relevant Frequente laag-risico variatie gaat een rol spelen bij screening en preventie Multifactoriële risicoschattingen zijn in ontwikkeling