A few thoughts on cancer and cancer family syndromes
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A few thoughts on cancer and cancer family syndromes
Pamela McGrann, MD.Department of Medical Genetics
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Family cancer syndromes
There are about 1.4 million new cancers diagnosed each year
~800,000 in men ~600,000 in women
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Cancer family syndromes Top 10 cancers Prostate Breast Lung and bronchus Colorectal lymphoma Bladder Melanoma Uterus Oropharynx renal
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Familial cancer syndromes
~ 30-40 % of adult deaths (nonaccidental, nonhomicidal) are due to cancer
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Cellular growth
Cells respond to:
External growth factors Steroid hormones Cell-cell interactions
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Cellular response to growth factors Cellular differentiation Cell growth Cell division Cell death (apoptosis)
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Development of cancer
Cancer occurs when an accumulation of gene mutations occur that affect:
Regulation of cell growth and cell division
Regulation of differentiation
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The Knudson hypothesis
Dr. Knudson studied retinoblastoma and noted:
Some tumors unilateral, some bilateral Some affected kids had a family hx of
retinoblastoma
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The Knudson hypothesis
The 2 hit theory of mutagenesis and cancer
PNAS 68(4):820-823, April 1971
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The Knudson hypothesis
In the inherited form: one mutation is inherited, and one is acquired.
In the noninherited form both mutations occur in somatic cells
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Tumor suppressor genes
The 1st tumor suppressor gene (RB1) was cloned in 1986
Homozygously inactive in all retinoblastoma tumors
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Tumor suppressor genes vs. oncogenes Tumor suppressor genes control cell growth If one copy is inactivated, the other copy
can still accomplish the task. Tumor suppressor genes act in a recessive
fashion
oncogenes originate from proto-oncogenes Examples: growth factors, growth factor
receptors, signal transduction proteins, nuclear transcription factors.
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Familial cancers characteristic features Several family members have the same or a
related cancer Early age at onset of cancer (~10 yrs earlier
than average age at onset of the cancer in the general population)
Presence of more than 1 type of cancer in a single family member
Multifocal onset or onset in paired organs
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Cancer family syndromes
Hereditary breast and ovarian cancer Autosomal dominant Accounts for 5-10% of breast and
ovarian cancers Genes – BRCA1 on chromosome
17q21 BRCA2 on 13q12.3
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Cancer family syndromes BRCA1 and BRCA2 Gene frequency: BRCA1: 1/500-
1/1000 BRCA2: unknown BRCA1 cancer risks: breast cancer
87% by age 70 yrs. 44% ovarian cancer risk by age 70 20% risk prostate cancer 2-4% pancreatic cancer (nl <1%)
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BRCA2
breast cancer risk - 84% by age 70 Ovarian cancer risk - 27% by age 70 Male breast cancer risk - 6% by age
70
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Familial adenomatous polyposis Autosomal dominant Incidence: 1/6000 – 1/13,000 (25-30%
are spontaneous new mutations) Gene: APC Location: 5q21q22 Diagnostic features: hundreds to
thousands of colonic polyps
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Familial adenomatous polyposis Polyps: as early as 7
years, as late as 70 yrs Most FAP patients
have polyps by the late teens
100% risk for colon ca by midforties
Polyps may be in duodenum and stomach too
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Lynch syndrome
Autosomal dominant Accounts for 5 – 10% of colon cancers Genes: MLH1 at 3p21.3 MSH2 2p21 PMS1 2q32.2 PMS2 7p22 MSH6 2p16.3
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Lynch syndrome: function of the genes involved
Not tumor suppressor genes or oncogenes Lynch is due to DNA mismatch repair genes
MMR genes encode enzymes that survey newly replicated DNA for errors and repair mismatched bases in the DNA
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Lynch syndrome: the cancers Colon Endometrial Transitional cell cancers of the renal
collecting system Pancreatic Ovarian
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Lynch syndrome: penetrance
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Lynch syndrome
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The first of our 4 grads this spring!