Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of...
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![Page 1: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/1.jpg)
Introduction to Cancer Genetics and Genomics
Apostolos Psychogios, MD, FACMG
Associate Professor of Pediatrics
LeeAnne Brown Chair of Clinical Excellence
Division of Medical Genetics and Genomic Medicine
![Page 2: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/2.jpg)
Disclosure Statement of Financial Interest
• I, Apostolos Psychogios, DO NOT have a financial
interest/arrangement or affiliation with one or more organizations
that could be perceived as a real or apparent conflict of interest in
the context of the subject of this presentation.
• I, Apostolos Psychogios, DO NOT anticipate discussing the
unapproved/investigative use of a commercial product/device
during this activity or presentation.
![Page 3: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/3.jpg)
Learning Objectives
• Identify the genetic syndromes associated with breast, ovarian, colon
and other types of cancer and the genes associated with these
syndromes.
• Use and understand the models available to predict risk of breast and
colon cancer.
• Understand the principles of genetic testing for individuals and families
where hereditary cancer predisposition is suspected.
• Recognize when to refer an individual or family for cancer genetics
evaluation
• Understand the management options for individuals who are carriers of
deleterious gene mutations
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![Page 5: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/5.jpg)
Inherited Predisposition to Cancer
• Inherited cancers range from 1-60%.
• For most tumor types, e.g. breast, the inherited
fraction fall in the range of 1-10%.
• Several rare tumors, adrenocortical carcinoma,
retinoblastoma, and optic gliomas have very
high inherited fraction (40-60%).
• Autosomal dominant inheritance
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Inheritance Patterns
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>10% Germline Mutations and Tumors
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Multiple Mechanisms: Wilm’s Tumor
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Multiple Mechanisms: Renal Cell Cancer
• Von Hippel Lindau Syndrome (VHL) – almost always clear cell histology
• 80% of sporadic RCC has somatic VHL mutations. Balanced translocation carriers involving chromosome 3
• Papillary renal carcinoma – due to activating mutations in c-MET oncogene
• Hereditary leiomyomatosis RCC: mutations in fumarate hydratase; autosomal dominant uterine fibroids and cutaneous leiomyomata
• Birt-Hogg-Dubé Syndrome – chromophobe/oncocytic
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Multiple Cancers: Birt-Hogg-Dubé Syndrome
• Chromophobe/oncocytic
histology RCC
• Benign fibrofolliculomas
• Colonic polyps
• Medullary thyroid cancer
• Spontaneous pneumothorax
• BHD tumor suppressor gene
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NEJM 359;7 August 14, 2008
Chromosomal Abnormalities in Human Cancer
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Example of Imprecise Translocation: t(8;14) in Burkitt’s Lymphoma
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Example of Precise Translocation: Philadelphia Chromosome in CML
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Precise Translocation: t(11;22) in Ewings’ sarcoma
Large destructive lesion in the diaphysis or metaphysis with a moth-eaten
appearance periosteal lifting may give "onion skin" or "sunburst" appearance
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N Engl J Med 2008;359:2143-53.
Genes and Common Cancers
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Breast-Cancer Susceptibility Loci and Genes
N Engl J Med 2008;359:2143-53.
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N Engl J Med 2007;357:154-62.
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“Red Flags” for HBOC Syndrome
• Breast cancer diagnosed < 50 years
• Ovarian cancer
• Male breast cancer
• Two primary breast cancers
• “Triple-negative” breast cancer
• Ashkenazi Jewish ancestry
• Familial BRCA gene mutation
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Risk Prediction Models
• There are well established computer models to
predict:
– Risk of developing breast cancer for someone of “average” risk –
Gail Model.
– Risk of developing breast cancer based on family history – Claus
Tables.
– Likelihood that genetic testing will yield a mutation in BRCA1 or
BRCA2 – BRCAPro (US model) and BOADICEA (UK model).
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N Engl J Med 2007;357:154-62.
![Page 24: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/24.jpg)
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http://www.afcri.upenn.edu/itacc/penn2/
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Professional Societies Guidelines
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N Engl J Med 2007;357:154-62.
![Page 28: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/28.jpg)
Other Syndromes with Increased Risk for Breast Cancer
• Li-Fraumeni – average diagnosis 32 in p53 carriers
• Cowden’s syndrome – PTEN mutations assoc. with thyroid cancer, hamartomas, skin lesions
• Peutz-Jeghers – 32% by age 60
• Ataxia telangiectasia (ATM) heterozygotes.
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Li-Fraumeni Syndrome (LFS)
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Cowden Syndrome (CS)
• Breast Cancer risk (30% lifetime risk).
• Thyroid cancer (10% lifetime risk).
• Cerebellar dysplastic gangliocytoma
• Mucocutaneous lesions
• Trichilemmomas (facial)
• Papillomatous lesions
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Colorectal Cancer (CRC) Risks
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HNPCC Family Pedigree
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Hereditary Non-Polyposis Colon Cancer Lynch Syndrome
• Autosomal dominant CRC without polyposis associated with
endometrial cancer, bile duct, ovarian, ureteral and gliomas.
• ~70% lifetime risk of CRC
• 50-70% endometrial cancer in classic Lynch.
• Right-sided CRC cancer is more frequent.
• Better prognosis of CRC stage for stage.
• Patients with 2 or 3 different primary HNPCC-related tumors.
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“Red Flags” for an Affected Individual with HNPCC
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Family History (Unaffected Individual) Criteria for HNPCC
Amsterdam Criteria (CRC based) - Exclude FAP
I. At least one CRC < age 50
II. Two affected generations
III. Three affected relatives, two are FDR relatives of other one
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HNPCC Genes
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Polyposis Syndromes
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“Red Flags” for Polyposis Syndromes
• More than 10 cumulative colorectal adenomas
• Colorectal cancer associated with multiple adenomas
• Familial mutation for hereditary polyposis syndrome
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HNPCC vs. AFAP vs. MAP
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Polyposis Associated with FAP
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MYH-Associated Polyposis
ACMG Genetics Review Course
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Colorectal Cancer Management
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“Red Flags” for Hereditary Melanoma
• Two or more melanomas in the proband or family (FDR)
• Melanoma and pancreatic cancer in the proband or family
• Family history of p16 gene mutation
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Hereditary Melanoma
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Genomics and the Continuum of Cancer Care
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NEJM 2011;364:340-50.
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N Engl J Med 2011;364:340-50.
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N Engl J Med 2008;358:1148-59
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N Engl J Med 2008;358:1148-59
![Page 52: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/52.jpg)
N Engl J Med 2008;358:1148-59
![Page 53: Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence.](https://reader034.fdocuments.net/reader034/viewer/2022042702/56649d195503460f949ee374/html5/thumbnails/53.jpg)
Quillen Genomic Medicine Program
Research
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LeeAnne Brown Research Project
• In collaboration with Mayo Clinic (Dr. Eric Wieben) 2012-
2015
• Whole Exome Sequencing/Methylation Analysis of patients
with:
– Unknown syndromes
– Autism, intellectual disability
– Neurologic disorders (MS, ALS, AD)
– Tumors (Multiplex families with breast, prostate, bladder cancer)
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Questions?