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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