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

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

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

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

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

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

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

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

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

10. The Knudson hypothesis The Knudson hypothesis In the inherited form: one mutation is inherited, and one is acquired. In the inherited form: one mutation is inherited, and one is acquired. In the noninherited form both mutations occur in somatic cells In the noninherited form both mutations occur in somatic cells

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

15. Tumor suppressor genes vs. oncogenes Tumor suppressor genes vs. oncogenes Tumor suppressor genes control cell growth Tumor suppressor genes control cell growth If one copy is inactivated, the other copy can still accomplish the task. If one copy is inactivated, the other copy can still accomplish the task. Tumor suppressor genes act in a recessive fashion Tumor suppressor genes act in a recessive fashion oncogenes originate from proto-oncogenes oncogenes originate from proto-oncogenes Examples: growth factors, growth factor receptors, signal transduction proteins, nuclear transcription factors. Examples: growth factors, growth factor receptors, signal transduction proteins, nuclear transcription factors.

16. Familial cancers characteristic features Familial cancers characteristic features Several family members have the same or a related cancer 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) 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 Presence of more than 1 type of cancer in a single family member Multifocal onset or onset in paired organs Multifocal onset or onset in paired organs

17. Cancer family syndromes Cancer family syndromes Hereditary breast and ovarian cancer Autosomal dominant Autosomal dominant Accounts for 5-10% of breast and ovarian cancers Accounts for 5-10% of breast and ovarian cancers Genes – BRCA1 on chromosome 17q21 Genes – BRCA1 on chromosome 17q21 BRCA2 on 13q12.3 BRCA2 on 13q12.3

18. Cancer family syndromes BRCA1 and BRCA2 Cancer family syndromes BRCA1 and BRCA2 Gene frequency: BRCA1: 1/500- 1/1000 Gene frequency: BRCA1: 1/500- 1/1000 BRCA2: unknown BRCA2: unknown BRCA1 cancer risks: breast cancer 87% by age 70 yrs. BRCA1 cancer risks: breast cancer 87% by age 70 yrs. 44% ovarian cancer risk by age 70 44% ovarian cancer risk by age 70 20% risk prostate cancer 20% risk prostate cancer 2-4% pancreatic cancer (nl <1%) 2-4% pancreatic cancer (nl <1%)

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

20. Familial adenomatous polyposis Familial adenomatous polyposis Autosomal dominant Autosomal dominant Incidence: 1/6000 – 1/13,000 (25-30% are spontaneous new mutations) Incidence: 1/6000 – 1/13,000 (25-30% are spontaneous new mutations) Gene: APC Gene: APC Location: 5q21q22 Location: 5q21q22 Diagnostic features: hundreds to thousands of colonic polyps Diagnostic features: hundreds to thousands of colonic polyps

21. Familial adenomatous polyposis Familial adenomatous polyposis Polyps: as early as 7 years, as late as 70 yrs Polyps: as early as 7 years, as late as 70 yrs Most FAP patients have polyps by the late teens Most FAP patients have polyps by the late teens 100% risk for colon ca by midforties 100% risk for colon ca by midforties Polyps may be in duodenum and stomach too Polyps may be in duodenum and stomach too

22. Lynch syndrome Lynch syndrome Autosomal dominant Autosomal dominant Accounts for 5 – 10% of colon cancers Accounts for 5 – 10% of colon cancers Genes: MLH1 at 3p21.3 Genes: MLH1 at 3p21.3 MSH2 2p21 MSH2 2p21 PMS1 2q32.2 PMS1 2q32.2 PMS2 7p22 PMS2 7p22 MSH6 2p16.3 MSH6 2p16.3

23. Lynch syndrome: function of the genes involved Lynch syndrome: function of the genes involved Not tumor suppressor genes or oncogenes Not tumor suppressor genes or oncogenes Lynch is due to DNA mismatch repair genes 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 MMR genes encode enzymes that survey newly replicated DNA for errors and repair mismatched bases in the DNA

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

25. Lynch syndrome: penetrance Lynch syndrome: penetrance

26. Lynch syndrome Lynch syndrome

27. The first of our 4 grads this spring!