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
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.
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
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
Inheritance Patterns
>10% Germline Mutations and
Tumors
Multiple Mechanisms: Wilm’s Tumor
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
Multiple Cancers: Birt-Hogg-Dubé Syndrome
•
Chromophobe/oncocytic
histology RCC
•
Benign fibrofolliculomas
•
Colonic polyps
•
Medullary thyroid cancer
•
Spontaneous
pneumothorax
•
BHD tumor suppressor
gene
Chromosomal Abnormalities in
Human Cancer
NEJM 359;7 August 14, 2008
Example of Imprecise Translocation:
Imprecise
Fusions
t(8;14) Lymphoma
t(8;14)
in Burkitt’s
t(8;14) in Burkitt
Burkitt’s
s Lymphoma
c-Myc proto-oncogene at 8q24
Chromosome 8
t(8;14) in Burkitt
Burkitt’s
sL
Images from M. Folsom, R. Naeem, Cytogenetics Laboratory, TCH
IgG locus at 14q32
Chromosome 14
ACMG Genetics Review Course June 2-5, 2011
IgG – c-M
Myc
t(8;14) Translocation
Activation of c-Myc oncogene by juxtaposition of c-Myc with
the Immunoglobulin
g
locus in lymphoid
y p
cells in Burkitt’s
Lymphoma – no fusion protein is made
ACMG Genetics Review Course June 2-5, 2011
Images from M. Folsom, R. Naeem, C
CML
Example of Precise Translocation:
Philadelphia Chromosome in CML
Images from R. Naeem, TCH
Philadelphia Chromosome in
CML
ACMG Genetics Review Course
Images from R. Naeem, TCH
June 2-5, 2011
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
Genes and Common Cancers
N Engl J Med 2008;359:2143-53.
Breast-Cancer Susceptibility
Loci and Genes
N Engl J Med 2008;359:2143-53.
N Engl J Med 2007;357:154-62.
“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
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).
N Engl J Med 2007;357:154-62.
http://www.afcri.upenn.edu/itacc/penn2/
Professional Societies Guidelines
N Engl J Med 2007;357:154-62.
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.
Li-Fraumeni Syndrome (LFS)
Cowden Syndrome (CS)
•
Breast Cancer risk (30% lifetime risk).
•
Thyroid cancer (10% lifetime risk).
•
Cerebellar dysplastic gangliocytoma
•
Mucocutaneous lesions
•
Trichilemmomas (facial)
•
Papillomatous lesions
Colorectal Cancer (CRC) Risks
HNPCC Family Pedigree
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.
“Red Flags” for an Affected Individual
with HNPCC
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
HNPCC Genes
Polyposis Syndromes
“Red Flags” for Polyposis Syndromes
• More than 10 cumulative colorectal adenomas
• Colorectal cancer associated with multiple
adenomas
• Familial mutation for hereditary polyposis
syndrome
HNPCC vs. AFAP vs. MAP
Polyposis Associated with FAP
MYH-Associated Polyposis
ACMG Genetics Review Course
Colorectal Cancer Management
“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
Hereditary Melanoma
Genomics and the Continuum
of Cancer Care
NEJM 2011;364:340-50.
N Engl J Med 2011;364:340-50.
N Engl J Med 2008;358:1148-59
N Engl J Med 2008;358:1148-59
N Engl J Med 2008;358:1148-59
Quillen Genomic Medicine Program
Research
LeeAnne Brown
Research Project
•
In collaboration with Mayo Clinic (Dr. Eric Wieben) 20122015
•
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)
Questions?