Combining genetic and exposure data significantly improves risk prediction for skin cancer
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1 Combining genetic and exposure data significantly improves risk prediction for skin cancer Pierre Fontanillas, Babak Alipanahi, Michaela Johnson, Catherine Wilson, 23andMe Research Team, Steve Pitts, Robert Gentleman, Adam Auton. 10/17/2018
2 Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the more common forms Melanoma is generally better studied due to its more aggressive nature 2
3 Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the more common forms Melanoma is generally better studied due to its more aggressive nature Epidemiological studies had identified main risk factors (UV exposure and pigmentation type) However, studies were generally small, tested a restricted set of risk factors, and did not use out-ofsample validation Difficult to build good predictive models 3
4 Replicate/identify risk factors for BCC, SCC, and melanoma In a large cohort Exposure risk factors Genetic risk score (GRS) Improve skin cancer prediction: Build the best predictive models [[ GxE interaction: GRS x Exposure ]] Out-of-sample validation 4
5 5M+ customers ~80% consent to research 75% 1 survey 1.5 B+ survey questions answered 23andMe cohort 1.6M genotyped variants 57M imputed variants 5
6 New cancer survey containing 72 questions: Personal history of cancer 34 questions - Type of cancer - Age of diagnosis - Body location - Diagnosis type - Treatments Risk factors 23 questions - Eye, hair, and skin colors - Freckles - Moles - Skin response to sun exposure - Sunbathing frequency - Typical weekly sun exposure Family history of cancer 16 questions - Cancer history of relatives (father, mother, siblings, and children) Usher-Smith, J.A., et al. (2014). Risk prediction models for melanoma: A systematic review. Cancer Epidemiol Biomarkers Prev 23(8): Olsen, C.M., et al. (2015). Independent validation of six melanoma risk prediction models. Journal of Investigative Dermatology 135 (5)
7 88,985 23andMe participants of European ancestry All European ancestry 103,008 23andMe participants of European ancestry 7
8 Generalized linear models: BCC SCC Melanoma (cases / controls) Personal history of cancer 34 questions - Type of cancer - Age of diagnosis - Body location - Diagnosis type - Treatment New cancer survey Risk factors 23 questions - Eye, hair, and skin colors - Freckles - Moles - Skin response to sun exposure - Sunbathing frequency - Typical weekly sun exposure Family history of cancer 16 questions - Cancer history of relatives (father, mother, siblings, and children) 608 phenotypes from 23andMe database morphology cognitive sensation eyes blood cardiovascular neurological pregnancy autoimmunerenal immune sports personality lifestyle addiction sleep drug_usage longevity food_preference gastrointestinal endocrine cancer pigmentation infection hair skin diet metabolic psychiatric teeth reproductive ~ Skin color + Large moles + Sunbathing frequency + BMI + parkinson respiratory drug_side musculoskeletal 8
9 Generalized linear models: BCC SCC Melanoma Personal history of cancer 34 questions - Type of cancer - Age of diagnosis - Body location - Diagnosis type - Treatment Genetic ~ Demographic + Risk + Score New cancer survey Risk factors 23 questions - Eye, hair, and skin colors - Freckles - Moles - Skin response to sun exposure - Sunbathing frequency - Typical weekly sun exposure Family History of skin cancer Family history of cancer 16 questions - Cancer history of relatives (father, mother, siblings, and children) 608 phenotypes from 23andMe database morphology cognitive sensation eyes blood cardiovascular neurological pregnancy autoimmunerenal immune sports personality lifestyle addiction sleep drug_usage longevity food_preference gastrointestinal endocrine cancer pigmentation infection hair skin diet metabolic psychiatric teeth reproductive + Moles + Susceptibility + Exposure + Misc. parkinson respiratory drug_side musculoskeletal Best Model: 32 factors Age Sex Ancestry 1 factor 1 factor 4 factors 8 factors 8 factors 7 factors 9
10 BCC SCC Melanoma Number of variants in GRS: - BCC: 47 - SCC: 14 - Melanoma: 18 23andMe risk prediction pipeline: Multhaup M.L. et al. (2017). The science behind 23andMe's Genetic Weight report. 10
11 Age Melanoma SCC BCC Moles Genetic Risk Score Total deviance explained by best models (32 factors): - Melanoma: 19.9% - SCC: 20.0% - BCC: 21.8% Exposure Susceptibility Family history Ancestry Miscellaneous Sex Deviance explained
12 Dysplastic moles Actinic keratosis before age of 40 Presence of large moles Moles in your right arm Age Moles Melanoma Melanoma BCC SCC BCC Genetic Risk Score Exposure Susceptibility Family history Ancestry Miscellaneous Sex Deviance explained
13 Melanoma BCC SCC 13
14 Dysplastic moles Actinic keratosis before age of 40 Presence of large moles Moles in your right arm Age Moles Melanoma Melanoma SCC BCC SCC BCC Sunbathing frequency before age of 30 Adulthood latitude Physical activity Typical sun exposure per week Childhood latitude Tanning bed Outdoor job Adulthood elevation Skin, hair, and eye colors Freckling tendency Blisters caused by sunburns Skin response to 3-4 hours of sun exposure Sun hair lightening Skin response to sun exposure without sun protection Genetic Risk Score Exposure Susceptibility Family history Ancestry (PCs) Miscellaneous Sex BMI Alcohol consumption Weight Smoking Morning person Desk clean person Seasonal allergies Deviance explained
15 Melanoma SCC BCC 15
16 a b c d a b c d 16
17 a b c d a b c d Melanoma: 25 predictive models reviewed; AUC = Usher-Smith, J.A., et al. (2014). Risk prediction models for melanoma: A systematic review. Cancer Epidemiol Biomarkers Prev 23(8):
18 18
19 4.7x 8.1x 11.7x 19
20 2.4x 2.5x 2.1x 20
21 3% 2% 1% 2x 2x 2x 21
22 % of high risk individuals with >2 fold prevalence increase (relative to mean prevalence) Risk factor BCC SCC Melanoma GRS 3% 2% 1% GRS + Exposure 5% 4% 1% Demographics (age + sex + ancestry) 6% 21% 12% Total 25% 31% 32% 22
23 4.9 years Age of diagnosis 7.5 years 7.2 years 7.4 years 23
24 New cancer survey + 100K samples training set 32 risk factors in predictive models Out-of-sample validation (90K samples) 24
25 New cancer survey + 100K samples training set 32 risk factors in predictive models Out-of-sample validation (90K samples) BCC, SCC and melanoma have similar risk factors, Melanoma quantitatively different 25
26 New cancer survey + 100K samples training set 32 risk factors in predictive models Out-of-sample validation (90K samples) BCC, SCC and melanoma have similar risk factors, Melanoma quantitatively different Genetic and exposure risk scores identified individuals at high risk for skin cancer [[ Absence of large GxE (no evidence for GRS x Exposure) ]] 26
27 Acknowledgements 23andMe research participants 23andMe Research Team: Michelle Agee Babak Alipanahi Adam Auton Robert K. Bell Katarzyna Bryc Sarah L. Elson Pierre Fontanillas Nicholas A. Furlotte David A. Hinds Bethann S. Hromatka Yunru (Claire) Huang Karen E. Huber Aaron Kleinman Nadia K. Litterman Matthew H. McIntyre Joanna L. Mountain Carrie A.M. Northover Steven J. Pitts Cody Sam J. Fah Sathirapongsasuti Olga V. Sazonova Janie F. Shelton Suyash Shringarpure Chao Tian Joyce Y. Tung Vladimir Vacic Catherine H. Wilson 23andMe employees 27
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