A few thoughts on cancer and cancer family syndromes

1. A few thoughts on cancer and cancer family syndromes Pamela McGrann, MD. Department of Medical Genetics

2. Family cancer syndromes • There are about 1.4 million new cancers diagnosed each year • ~800,000 in men • ~600,000 in women

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

4. Familial cancer syndromes • ~ 30-40 % of adult deaths (nonaccidental, nonhomicidal) are due to cancer

5. Cellular growth Cells respond to: • External growth factors • Steroid hormones • Cell-cell interactions

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

7. Development of cancer Cancer occurs when an accumulation of gene mutations occur that affect: • Regulation of cell growth and cell division • Regulation of differentiation

8. The Knudson hypothesis Dr. Knudson studied retinoblastoma and noted: • Some tumors unilateral, some bilateral • Some affected kids had a family hx of retinoblastoma

9. The Knudson hypothesis • The 2 hit theory of mutagenesis and cancer • PNAS 68(4):820-823, April 1971

10. 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

13. Tumor suppressor genes • The 1st tumor suppressor gene (RB1) was cloned in 1986 • Homozygously inactive in all retinoblastoma tumors

15. 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.

16. 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

17. 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

18. Cancer family syndromesBRCA1 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%)

19. BRCA2 • breast cancer risk - 84% by age 70 • Ovarian cancer risk - 27% by age 70 • Male breast cancer risk - 6% by age 70

20. 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

21. 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

22. 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

23. 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

24. Lynch syndrome: the cancers • Colon • Endometrial • Transitional cell cancers of the renal collecting system • Pancreatic • Ovarian

25. Lynch syndrome: penetrance

26. Lynch syndrome

27. The first of our 4 grads this spring!