A few thoughts on cancer and cancer family syndromes

Pamela McGrann, MD.Department of Medical Genetics

Family cancer syndromes

There are about 1.4 million new cancers diagnosed each year

~800,000 in men ~600,000 in women

Cancer family syndromes Top 10 cancers Prostate Breast Lung and bronchus Colorectal lymphoma Bladder Melanoma Uterus Oropharynx renal

Familial cancer syndromes

~ 30-40 % of adult deaths (nonaccidental, nonhomicidal) are due to cancer

Cellular growth

Cells respond to:

External growth factors Steroid hormones Cell-cell interactions

Cellular response to growth factors Cellular differentiation Cell growth Cell division Cell death (apoptosis)

Development of cancer

Cancer occurs when an accumulation of gene mutations occur that affect:

Regulation of cell growth and cell division

Regulation of differentiation

The Knudson hypothesis

Dr. Knudson studied retinoblastoma and noted:

Some tumors unilateral, some bilateral Some affected kids had a family hx of

retinoblastoma

The Knudson hypothesis

The 2 hit theory of mutagenesis and cancer

PNAS 68(4):820-823, April 1971

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

Tumor suppressor genes

The 1st tumor suppressor gene (RB1) was cloned in 1986

Homozygously inactive in all retinoblastoma tumors

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.

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

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

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%)

BRCA2

breast cancer risk - 84% by age 70 Ovarian cancer risk - 27% by age 70 Male breast cancer risk - 6% by age

70

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

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

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

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

Lynch syndrome: the cancers Colon Endometrial Transitional cell cancers of the renal

collecting system Pancreatic Ovarian

Lynch syndrome: penetrance

Lynch syndrome

The first of our 4 grads this spring!