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Hereditary Cancer
Cancer Answers Cancer Care Nova Scotia
May 20th, 2008
Patricia Steele, MSc, CCGC, CGCGenetic Counsellor
Maritime Medical Genetics ServicesIWK Health Centre
and
Genetic Testing
Outline
Cell Growth and Development Sporadic, Familial and Hereditary Quick Genetics Review Common Inherited Forms of Cancer Genetic Assessment Pros and Cons of Genetic Testing
Cell Growth and Development
Many processes control cell growth and cell division
Cell division – making an exact copy of itself
DNA content doubled and then divided into both cell copies
Many genes involved
Cancer – Abnormal Cell Growth
Cancer is the abnormal growth of cells during cell division
Cancer results from defects or damage in genes (DNA) involved in cell division
Several of these controls need to be damaged before a cell becomes cancerous
Cancer: When is it Inherited?~ 85% Sporadic (by
chance)~ 10% Familial~ 5% Hereditary
Hereditary - ~5%
Familial- ~10%
Sporadic - ~85%
Sporadic Cancer History
Occurs by chance alone 1 or 2 individuals at
typical age of onset Not an inherited pattern Relatives usually not at
increased chance to develop cancer (general population chance)
Genetic testing not beneficial
Familial Cancer History
Not the same type of cancer or related cancers
Average age of onset No clear pattern of inheritance May be due to shared factors
(genes/environment/lifestyle) Relatives have slightly
increased chance of cancer Genetic testing not beneficial
Many family members with the same or related cancers
Earlier ages of onset One person may have
more than one type cancer Two or more generations
affected Genetic testing may be
beneficial
Hereditary Cancer History
Quick Genetic Review
The genome is like an encyclopedia...
A Gene is Like A Recipe for Making A Specific
Protein
Everyone Has Changes In Their DNA
Some changes have no medical effect
A harmful change in the DNA is called a ‘mutation’
Mutations prevent the gene from working properly
Some Gene Mutations Cause A Loss of Function of the Gene
Tumor suppressor genes instruct the cells to stop cell division
A mutation in a tumour suppressor gene is like having the brakes fail in your car
Some Gene Mutations Cause A Gain of Function of the
Gene
Oncogenes -initiate cellular division (promote cell growth)
A mutation in an oncogene can speed up cell growth
Like pressing on the gas peddle of a car all the time (out of control)
Some Genes Repair DNA Errors (The DNA Mechanics)
Many Cellular Changes Involved
Inherited or AcquiredGene Mutations
Dominant Inheritance
does not cause cancer increases risk for developing cancer
Inherited Cancer Syndromes
Hereditary component in ~ 5-15% of these very common types of cancers
Colorectal Cancer Breast/Ovarian Cancer
Less common inherited cancer syndromes Hereditary Diffuse Gastric Cancer
(HDGC) Multiple Endocrine Neoplasia (MEN) Li-Fraumeni syndrome Von Hippel Lindau syndrome
Inherited Colon Cancer
Hereditary nonpolyposis colon cancer (HNPCC)
Familial adenomatous polyposis (FAP) ~ 1% of hereditary colon cancer Attenuated FAP (later age onset)
MYH Associated Polyposis (MAP) ~ 1% of hereditary colon cancers
Hereditary NonpolyposisColon Cancer (HNPCC)
Small number of polyps
Many DNA repair genes involved
Also called Lynch syndrome Type 1– Colon cancer
Type 2- Colon Uterine, breast, pancreas, ovarian, bile
duct
Familial Adenomatous Polyposis (FAP)
~1% hereditary colon cancers Hundreds of polyps
Onset of polyps - teen years Start screening no later than age 10 Average age of cancer diagnosis – age 38
If no treatment – v. high likelihood of cancer
Attenuated FAP (AFAP) multiple polyps Later age onset of colon cancer (<60 years)
APC gene - good detection rate (~80-90%)
MYH-Associated Polyposis (MAP)
Families with multiple polyps (like AFAP) But do not identify APC gene mutation
2002 - new gene found – MYH ~10% of AFAP-like families
Screening beginning in 20’s Recessive inheritance
inherit 2 non-working genes See in siblings
Routine Screening ?Increased
Screening? Most people:
~ 5-6% lifetime chance of colon cancer Later ages of onset > 10 years from polyp to bowel cancer
If no family history of colon cancer then general population screening is appropriate
Colon screening after age 50 Fecal Occult Blood Test (FOBT)
If family history or inherited predisposition then more direct screening is appropriate
Colon screening with more direct test (i.e. colonoscopy) Start 5-10 years earlier than onset in the family
Sporadic Breast Cancer
All women have a 1 in 9 (11%) lifetime chance of developing breast cancer usually over 65 years-of-age
Most women over-estimate their risk for breast cancer and genetic testing is not beneficial or appropriate for most women
Hereditary Breast/Ovarian Cancer
Family History How closely related - 1st or 2nd degree
relatives Early ages of onset
Average age of onset ~39-44years More than one primary cancer Ancestry (Icelandic, Ashkenazi Jewish) Laterality (one side or both sides) Male breast cancer
Breast Cancer Genes(BRCA1 and BRCA2)
Increased Predisposition but not a diagnosis
If BRCA mutation found: Genetic testing is available for family
members
If no BRCA mutation found: No genetic test available for family
members
If ‘Positive’ for BRCA Mutation
Additional Options to consider: Increased screening
Clinical breast exams 2 times a year MRI Mammograms start 5-10 years earlier than onset in
family
Lifestyle changes ? Quit smoking Healthy eating and exercise?
Medical prevention Prophylactic surgery
Mastectomy Oophorectomy
Breast Cancer Genes
Gene
BRCA1 (breast, ovarian, prostate)
BRCA2 (male/female breast, ovarian)
TP53 (breast, brain, sarcoma, leukemia, adrenal)
PTEN (breast, thyroid, oral, intestinal)
ATM (breast, ionizing radiation sensitivity)
Undiscovered genes
Contribution to Hereditary Breast
Cancer
20%–40%
10%–30%
<1%
<1%
<1%
30%–70%
Hereditary Diffuse Gastric Cancer(HDGC)
5%-10% of all gastric (stomach) cancers are familial Gastric cancer seen in several other cancer
syndromes (i.e. HNPCC) Diffuse - Different pathology (not a tumour mass) Stomach wall – rubbery, hard, thickened Average age onset – 38 years Also see:
Lobular breast cancer Colon cancer
CDH1 gene
Tools for Genetic Assessment
Family history best predictor Maternal & paternal history
How closely related Specific types and specific patterns
Clinical and pathology information Tumour pathology
Breast cancer - lobular or infiltrating ductal Colon cancer – many polyps or a few polyps
Confirming the diagnosis Was it ovarian cancer or cervical cancer?
Multiple Endocrine Neoplasia (MEN)
Multiple endocrine neoplasia type 1 (MEN1) Pituitary, pancreas, parathyroid tumors MEN1 gene (chromosome 11)
Multiple endocrine neoplasia type 2 (MEN2) Medullary thyroid cancer (~75% sporadic) Adrenal gland tumours (pheochromocytoma) Parathyroid disease RET gene (chromosome 10)
Genetic Counselling…..What to Expect
Before an appointment:
Your homework: Family History Questionnaire Medical records
Our homework: Family specific genetic assessment Select specific genetic test – if
available
Not Always An Obvious Pattern-
Need the Full (Family) Picture Li-Fraumeni syndrome
Breast cancer Other cancers in the family
Bone cancer (Osteosarcoma) Soft tissue cancers (Sarcoma) Leukemia
Von Hippel Lindau syndrome Benign tumours of brain/spine
(Hemangioblastoma) Kidney cancer (renal cell) Adrenal glands
Genetic Testing Limitations
Not a ‘yes’ or ‘no’ answer Not 100% detection rate Technical limitations? Other genes to be discovered? Interpretation of result is unclear
Not all at-risk families are able to be tested
1st need to test an appropriate, living affected individual
Based on referral criteria for BRCA testing: ~ 10% of individuals tested have mutation found ~90% results - ‘no mutation found’
Dx 35D 43 yr
Some Benefits of Genetic Testing
Identifies high-risk individuals
May help in decision-making (medical/lifestyle)
Screening and prevention strategies
May explain cancer pattern if mutation found
May have positive impact family relationships
May relieve anxiety
Some Reasons Not to HaveGenetic Testing
You “wouldn’t do anything different” Genetic testing does not detect all
mutations Despite screening options, the cancer risk
not zero Privacy, insurance or employment
concerns? May increase fear/anxiety – open a
Pandora’s Box May negatively impact family relationships Guilt of ‘passing it on’
Review –The Clues That Cancer Might be
Inherited? Many individuals in a family
On the same side of the family Affected over many generations
Three generation family history Early ages of onset
Often before age 50 Specific patterns and related
types of cancer
Review –What’s Right for You?
Family Hx
Assessment
Personalized screening and prevention recommendations
Referral for Genetic Evaluationwith personalized screening and prevention recommendations
Standard screening and prevention recommendations
Intervention
Average(1 in 9)Sporadic
Moderate(Familial)
High(Hereditary)
Genetic Risk
Some Things to Remember
Everyone has 6-12 genes that don’t work properly – most not a health concern
The chance of developing cancer is never 100% and it is never 0%
Family history is important
But Family is more important!!
Thank You!
Patricia SteeleMaritime Medical Genetics
IWK Health CentreHalifax, NS
902-470-8754