Cancer, Genetics, Your Family, and You

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Cancer, Genetics, Your Family, and You
Marsha M. Goldstein Basson Memorial Fund
Inaugural Lecture and Reception October 25, 2008
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Basic Genetics
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Family history information and interpretation
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Family health information to gather

• Three generations
• Current age or age at the time of death
• Age at the time of diagnosis of cancer or other
  condition/disease
• Location of primary cancer
• Breast, colon, pancreas, ovary
• Lung, brain, bone
• Try to confirm when unsure or vague
• stomach ,abdominal

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Familial risk assessment
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Basic Cancer Genetics
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• All cancer is genetic,
• but
• not all cancer is hereditary

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Most cancer is not hereditary

• In general, most cancers are sporadic while
• roughly 5-10 are hereditary

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When does a family history suggest a hereditary
cancer predisposition?

• More than one generation of individuals affected
• Father (pancreatic cancer), daughter (breast
  cancer)?
• Child (brain cancer), mother (breast cancer)?
• Young age at diagnosis vs. age of diagnoses in
  general population
• premenopausal breast cancer before age 50
• Individuals in the family who have had more than
  one type of cancer
• pancreas and melanoma
• breast and ovarian
• colon and stomach

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When does a family history suggest a hereditary
cancer predisposition?

• Bilateral Cancers
• Breast
• May not be simultaneous
• Ovary
• Ocular (retinoblastoma)?
• Male breast cancer
• Ashkenazi Jewish ancestry

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When cancer is hereditary

• We inherit a predisposition to cancer, often
  increased greatly over the general population
• however
• This predisposition is not predestination

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Hereditary cancers and cancer syndromes
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Hereditary cancer syndromes

• Syndrome
• runs together (Greek)?
• set of detectable characteristics
• variable expression
• Rare vs. most presentations of a disease
• Important models for understanding more common,
  sporadic forms of diseases
• Lynch syndrome
• HNPCC
• Colon, endometrium, stomach, ovary, pancreas
• Several genes identified important in correcting
  DNA mistakes

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Hereditary cancer syndromes

• Breast-ovarian cancer syndrome
• BRCA1 and BRCA2
• Familial adenomatous polyposis (FAP)
• APC gene
• Hundreds to thousands of polyps in the colon
• Li-Fraumeni syndrome
• p53
• sarcomas

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Hereditary cancer syndromesand predisposition
syndromes

• Von Hippel-Lindau syndrome
• VHL gene
• malignant and benign neoplasms
• most frequently retinal, cerebellar, and spinal
  hemangioblastoma, renal cell carcinoma (RCC),
  pheochromocytoma, and pancreatic tumors
• Peutz-Jeghers syndrome
• Cowden disease
• Hamartomatous polyps and predisposition to
  malignancy

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Genes have been implicated in a number of cancers
that can occur in families

• Thyroid cancer
• Melanoma
• Brain cancer
• Several genes associated with gliomas that occur
  independent of known syndromes
• Known syndromes with increased risk for brain
  cancer
• Neurofibromatosis-1 (NF1) and NF2
• Tuberous sclerosis
• Li-Fraumeni syndrome
• Prostate cancer
• several genes are involved in the origin and/or
  progression of this neoplasm
• Many additional genome regions likely have more
  genes yet to be identified

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Pancreatic Cancer

• In 2008, over 38,000 Americans will be diagnosed
  with pancreatic cancer and nearly 34,000 will die
• The 5 year survival rate is less than 5 percent
  and has remained largely unchanged in the last
  thirty years
• Despite the sobering statistics, less than 2
  percent of the National Cancer Institutes
  federal research funding is currently allocated
  to pancreatic cancer

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Hereditary Pancreatic Cancer

• Familial pancreatic cancer
• About 10 of all pancreatic cancer
• Significantly increased PC risk depending on
  number of FDR affected
• palladin, ?????
• Hereditary breast-ovarian cancer syndrome
• BRCA2
• 3-10 pancreatic cancer risk
• FAMMM syndrome
• Familial atypical multiple mole melanoma
• PC (15-20 risk) and melanoma
• CDKN2A

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Hereditary Pancreatic Cancer

• Peutz-Jeghers syndrome
• PC risk 36
• Skin pigmentation GI hamartomas colon, ovarian,
  breast, stomach cancer
• STK11
• Other syndromes with likely increased PC risk
• Lynch syndrome
• Ataxia telangiectasia
• Li-Fraumeni syndrome

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Pancreatitis and Pancreatic cancer

• Inflammation of the pancreas
• 26-fold increased risk of pancreatic cancer when
  chronic
• Environmental factors, infections, injury
• 4/100,000
• Sjogren syndrome
• Hyperparathyroidism-jaw tumor syndrome
• Metabolic diseases
• Homocystinuria
• Familial pancreatitis
• 50-fold risk of developing pancreatic cancer (40
  by age 70.2)?
• PRSS1, SPINK1, chymotrypsin C gene variants
• Idiopathic pancreatitis
• Mutations in the CFTR (cystic fibrosis) gene
• CF most common Caucasian genetic disease

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Screening for pancreatic cancer

• Various approaches have been proposed
• no consensus regarding frequency
• Best when applied to those with
• Strong family history
• Chronic pancreatitis
• Absence of symptoms
• Tumor markers measured in blood
• CA19-9 and CEA
• Endoscopic ultrasonography (EUS)?
• Highly sensitive
• CT or MRI scan
• MRCP
• Magnetic resonance cholangiopancreatography
• Accurate noninvasive better for finding
  obstruction

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Cancer Genetics and the Ashkenazim
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To test or not to test?...........
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• Testing should begin with an affected individual

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Assess risk and screen appropriately
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Familial risk assessment
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Assessing your family health history
Personalized prevention recommendations
referral for further evaluation
High Risk
Family Health History
Moderate Risk
Personalized prevention recommendations
Reinforce standard prevention recommendations
Average Risk
Scheuner, et al. Am J Med Genet (1997), 71315-324
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General Recommendations for Reducing Cancer Risk

• Maintain a healthy body weight
• Do not use tobacco products avoid excessive
  alcohol consumption
• Exercise regularly
• Eat a diet that is high in fiber
• Avoid excessive sun exposure (use sunscreen)?
• Perform regular self-examinations
• See your doctor for periodic screenings
  (mammograms, colonoscopies, prostate exams)?
• If cancer runs in your family, discuss this
  information with your doctor

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General population cancer screening
guidelinesAmerican Cancer Society

• Women
• Yearly mammograms - age 40
• Clinical breast exam (CBE)
• every 3 years for women in their 20s and 30s
• every year for women 40 and over
• Breast self-exam (BSE) an option starting in 20
• Cervical cancer screening by age 21 years old
• Pap test every 1-2 years depending on method of
  test
• Uterine cancer
• Speak to your doctor if you are postmemopausal

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General population cancer screening
guidelinesAmerican Cancer Society

• Men
• Prostate Cancer Screening
• prostate-specific antigen (PSA) blood test and
  digital rectal examination should be offered
  annually, beginning at age 50
• Men at high risk should begin testing at age 45
• African-American men
• men with a strong family of one or more
  first-degree relatives father, brothers
  diagnosed before age 65
• Men at even higher risk could begin testing at
  age 40
• multiple first-degree relatives affected at an
  early age
• depending on the results of this initial test, no
  further testing might be needed until age 45.

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General population cancer screening
guidelinesAmerican Cancer Society

• Women and Men
• Colorectal Cancer Screening
• Beginning at age 50,average risk

Tests that find polyps and cancer flexible
sigmoidoscopy every 5 years  colonoscopy every
10 years  double contrast barium enema every 5
years  CT colonography (virtual colonoscopy)
every 5 years
Tests that mainly find cancer fecal occult blood
test (FOBT) every year fecal immunochemical
test (FIT) every year stool DNA test (sDNA),
interval uncertain
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Future Directions

• Further understand the genetic mechanisms of
  cancer development and how to compensate or
  manipulate them to reduce cancer occurrence
• Improve strategies for
• Screening
• Diagnosis
• Treatment
• Education, collaboration and advocacy
• Medical and scientific community
• Lay community
• The National Plan to Advance Pancreatic Cancer
  Research Act (H.R.7045)?

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Thank you
NOVEMBER IS PANCREATIC CANCER AWARENESS MONTH
Marsha M. Goldstein Basson Memorial Fund