Breast Cancer Susceptibility and HLA Complex: Source of Missing Heritability?

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1 Breast Cancer Susceptibility and HLA Complex: Source of Missing Heritability? M. Tevfik DORAK Environmental & Occupational Health College of Public Health Florida International University Miami, USA Cancer Institute of New Jersey December 7, 2011

2 Outline Breast Cancer Susceptibility & GWAS GWAS & Missing Heritability GWAS Myths HLA & Breast Cancer Susceptibility

3 Breast Cancer Susceptibility K McPherson, CM Steel, JM Dixon. BMJ 2000;321(9):624-8

4 Breast Cancer Susceptibility

5 Cumulatively, no more than 60% of women with a BRCA1/2 mutation will develop breast cancer by age 80. Breast Cancer Susceptibility & Genetics Frank SA. Nat Rev Genetics 2004;5:764-72

6 Breast Cancer Susceptibility & Genetics Stratton & Rahman. Nat Genet 2008;40(1):17-21

7 Breast Cancer Susceptibility & GWAS

8 Breast Cancer Susceptibility & GWAS

9 Breast Cancer Susceptibility & GWAS

10 Breast Cancer Susceptibility & GWAS

11 Breast Cancer Susceptibility & GWAS

12 Outline Breast Cancer Susceptibility & GWAS GWAS & Missing Heritability GWAS Myths HLA & Breast Cancer Susceptibility

13 GWAS & Missing Heritability

14 GWAS & Missing Heritability (www)

15 Why Did GWAS Disappoint?

16 Why Did GWAS Disappoint? Our strongest candidate gene CYP21A2 is in the class III region. but not included in GWAS because of the presence of a paralog in the genome

17 GWAS in Childhood Leukemia

18 GWAS Analysis

19 GWAS Analysis

20 Outline Breast Cancer Susceptibility & GWAS GWAS & Missing Heritability GWAS Myths HLA & Breast Cancer Susceptibility

21 GWAS Myths Genome-wide coverage of all genes and variants No need for candidate gene studies If GWAS do not find an association, no other study will find

22 What does GWAS Offer for HLA Associations

23 What does GWAS Offer for HLA Associations

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25 Outline Breast Cancer Susceptibility & GWAS GWAS & Missing Heritability GWAS Myths HLA & Breast Cancer Susceptibility

26 HLA & Breast Cancer Susceptibility What is the HLA complex and why is almost any disease risk associated with it? HLA & Breast Cancer Susceptibility Relevant non-hla genes

27 Why is There an HLA Association in Almost Any Disease? The very first MHC association was with leukemia in mice (1964) and with Hodgkin disease in humans (1967) Many cancers show associations and some (NPC) even show linkage to MHC CAH and HH genes were first located in and around HLA by association studies Autoimmune disorders and infectious diseases show the strongest associations Besides, sarcoidosis, birth weight, obesity, long QT syndrome and many others show associations with HLA alleles or haplotypes

28 (in the 1980s, we did not know much about non-hla genes) But now we do! Shiina et al, 2004 (www)

29 Transcription Factors in the Extended MHC Ziegler, 2005 (www)

30 HLA Polymorphisms Highest resolution DNA level HLA alleles: Related to transplantation success, susceptibility to diseases related to antigen presentation (autoimmune disorders, infectious diseases) Serological HLA antigens: Relevant to transplantation and disease associations HLA epitopes (Bw4/Bw6; C1/C2): Interactions with NK cell Functional supertypes: Involved in antigen presentation Genetic supertypes: Represents ancestral lineages

31 HLA Polymorphisms Current disease association studies are mainly concerned with high resolution allelic associations and may miss out a lot of information Examination of functional groupings and lineages rather than individual alleles may be a more powerful approach

32 Functional Multi-allelic HLA Polymorphisms Functional supertypes Cross-reactive groups (CREGs) Codon 114 Codon 116 Bw4/Bw6 epitopes Functional supertypes Codon 114 Codon 116 C1/C2 epitopes Phylogenetic lineages Codon 86 Codon 57 Class III region HLA-C HLA-A HLA-B HLA- DRB3/4/5 HLA- DRB1 HLA- DQB1

33 Functional Multi-allelic HLA Polymorphisms SNPs 4+ digit alleles forming supertypes Specificities (2 digit) Phylogenetic groups DRB1*01 01/10 DRB1*03 DRB3 DRB1*04 DRB4 DRB1*07 DRB4 DRB1*08 DRB3 (08) DRB1*09 DRB1*10 DRB1*11 DRB1*12 DRB3 DRB3 DRB4 01/10 DRB1*13 DRB1*14 DRB1*15 DRB1*16 DRB3 DRB3 DRB5 DRB5

34 HLA-DR/DQ Region

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36 Human Major Histocompatibility Complex Most gene-dense region in the genome Xie, 2003 (www)

37 HLA & Breast Cancer Susceptibility

38 Non-HLA Genes of the HLA Complex Involved in Fundamental Cellular Processes

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41 MHC & DNA Repair

42 DDR1 DAXX Motoyama, 2004 (www) IEX-1 Nakamura Y. Cancer Sci 2004

43 DNA damage checkpoint machinery In response to DNA damage, ATM and ATR phosphorylate histone H2AX and thereby facilitate the recruitment and phosphorylation of mediators such as MDC1, 53BP1, BRCA1, and the MRE11 RAD50 NBS1 complex. Stalling of the DNA replication fork results in the recruitment of the ATR ATRIP complex by RPA. In turn, the formation of nuclear foci of mediator complexes promotes transmission of the DNA damage signal to downstream targets such as Chk1, Chk2, FANCD2, and SMC1. The PCNA-like RAD1 RAD9 Hus1 complex, the RFC-like RAD17, and Claspin may collaborate in checkpoint regulation by detecting different aspects of a DNA replication fork. The mismatch repair proteins MLH1 and MSH also implicate in the activation of ATM-Chk2 pathway. The kinases Chk1 and Chk2 phosphorylate effectors such as p53, CDC25A, and CDC25C and thereby delay cell cycle progression or induce senescence or apoptosis via activation of the G1 S, intra-s, or G2 cell cycle checkpoints. Thus, these DNA damage checkpoint mechanisms cooperate with DNA repair machinery to suppress genomic instability and cancer. Motoyama, 2004 (www)

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46 DAXX gene is within the HLA complex.

47 IEX1 / IER3 gene is within the HLA complex.

48 (in the 1980s, we did not know much about non-hla genes) But now we do! Shiina et al, 2004 (www)

49 CYP21A2 & Adrenal Sex Steroids Shiina et al, 2004 (www)

50 CYP21A2 & Adrenal Sex Steroids Estrogen exposure increases the risk for breast cancer After menopause, the only source of endogenous estrogen is adrenal sex steroids Adrenal sex steroid levels show associations with risk and prognosis

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52 Legraine, JCEM 2000 (www)

53 Adrenal Steroid Biosynthesis Pathway CHOLESTEROL CYP11A PREGNONOLONE CYP17 170H-PREGNONOLONE DHEA PROGESTERONE CYP21 17OH-PROGESTERONE CYP21 ANDROSTENEDIONE ESTRONE DEOXY- CORTICOSTERONE 11-DEOXYCORTISOL TESTOSTERONE ESTRADIOL CYP11B1 ALDOSTERONE CORTISOL DIHYDROTESTOSTERONE

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56 CYP21A2 gene contains common mutations that cause CAH In heterozygosity, these mutations increase DHEAS levels This gene is not included in any GWAS chip This gene has never been examined in breast cancer susceptibility studies

57 Can We Improve Breast Cancer Predictive Models? Yes, We Can - GWAS are not the ultimate tools as frequently thought - Most relevant markers are not included - Data analysis for GWAS wastes a lot of data - Heterozygote advantage, haplotype analysis and interactions are not considered - HLA complex data is overlooked

58 Conclusions - Current knowledge on genetic susceptibility to breast cancer is insufficient - GWAS has substantially contributed to the field, but is not the ultimate tool - Increasing the number of SNPs in covered regions is unlikely to improve the situation - HLA region is a strong candidate to harbor breast cancer susceptibility markers

59 Take Home Message - GWAS do not cover the whole genome - HLA complex contains biologically highly plausible candidate genes for breast cancer susceptibility - Filling the gaps of GWAS may be more productive than increasing the number of SNPs included in GWAS chips

60 Acknowledgments Cardiff, UK Birmingham, AL Newcastle, UK Hamilton, NJ Professor Alan K Burnett Professor Ken I Mills Dr Wenshuo Shao Dr Richard A Kaslow Professor Andy G Hall Professor Louise Parker Dr Caroline Relton Rachel MacKay Brittany Morrison Charronne Davis Esma Ucisik-Akkaya Dr Thuy Do Dr Grant Gallagher & Dr Eli Mordechai

61 Acknowledgments My current team: Amy, Sandeep & Malar (& Meredith) Florida International University RSCPHSW EOH

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