Gen14-Cancer Genetics I

Front 1

What can inc predilection to cancer?

Back 1

"Oncogenes, Chromosome Structure, Chromosome number (Aneuploidy), Molecules bound to DNA :, Epistatic changes, Tumor suppressor genes (*most inherited cancers)

Front 2

What is a proto-oncogene?

Back 2

Normal gene before it was mutated.

Front 3

Fcns of oncogenes? Examples?

Back 3

Apoptosis (telomerase genes), growth factors, transcription factors, angiogenesis - all regulatory mechanisms in a cell (which can be deregulated in a cancer cell). Eg Ras, myc, src

Front 4

Mech of telomerase as oncogene?

Back 4

"Repairs shortened chrom-> contin to divide-> malignant cell. Normally, short RNA primer doesn't line up on the 3’ end exactly & length of the primer is lost w/ each DNA replication-> chrom instability

Front 5

What is the origin of mutations in oncogenes?

Back 5

"Most are somatic. Constitutional are not gen found (except MET & RET). Result in up reg due to missense, amp, translocation, & promoter alteration-> gain of function. Genes not more prone to mutation

Front 6

Examples of inherited mnissense mutations

Back 6

MET & MEN2

Front 7

Charac of MET

Back 7

(7q31) – AD papillary renal cancer- activating mutations cause receptor to fcn as an active tyrosine kinase in absence of ligand. 2nd (& 3rd or 4th) hits needed for the cells to become clonal

Front 8

Charac of RET

Back 8

(10q11.2) – AD Multiple Endocrine Neoplasia 2 (MEN2) – spectrum of familial medullary thyroid cancer, MEN2A and MEN2B. Tyrosine kinase receptor binds glial cell growth factor & neurturin (loss of fx implicated in Hirchsprung). Genetic Testing standard of care. Med carcinoma of thyroid – thyrocalcitonin-producing tumor of parafollicular cells. 60 – 90%, Parathyroid adenomas & Pheochromocytomas

Front 9

Examples of amplification

Back 9

N-myc in neuroblastoma, Her2/neu & c-myc in breast (somatic). Detected by CGH

Front 10

Common cancers w/ translocations

Back 10

Hematopoetic cancers. Often involve a transcription factor. Eg Burkitt’s c-myc on chrom 8 is translocated to 2,14,or 22 at the site of the immunoglobin loci. Causes expression of c-myc

Front 11

Examples of aneuploidy causing cancer

Back 11

Trisomy 21: acute megakaryocytic leukemia. Mosaic Turner syndrome: gonadoblastoma (correlates with presence of Y chromosome). Klinefelter (XXY) male breast cancer.

Front 12

Example of chrom structural defects causing cancer

Back 12

WAGR (wilm’s tumor, aniridia, genital abnormalities, retardation): 11p13. WT1 gene deletion causes Wilm’s tumor. Children w/ deletion screened for renal tumors w/ ultrasound every 4 months until 5yo. Retinoblastoma: some caused by del13q14 region (1st hit)

Front 13

Example of epistatic changes causing cancer?

Back 13

"Beckwith-Wiedemann: imprinting on 11p15 @ telomeric domain (H19 & IGF2) & centromeric domain (KCNQ1, KCNQ1OT1, & CDKN1C)-> pre/post natal excessive growth (macroglossia, organomegaly, omphalocele, hernia, hemihyperplasia)

Front 14

What should Beckwith-Wiedemann patients be screened for?

Back 14

Wilms tumor (telomeric defects), hepatoblastoma, adrenocortical carcinoma, rhabdosarcoma (centromeric defect), & neurobalstoma. Via Physical exam, baseline CT or MRI & abdominal ultrasound, serum alpha fetoprotein, urinary calcium/creatinine ratio

Front 15

3 molec genetics concepts assoc w/ BWS

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Genomic Imprinting (methylation), Somatic mosaicism, Genetic heterogeneity

Front 16

Examples of sporadic tumors caused by somatic methylation

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Inactivate tumor suppressors. VHL in reanl cell carcinoma & MLH1 & MSH2 in colon/gastric ca

Front 17

Charac of familial retinoblastoma

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90% pentrance, 80% de novo. Gene encodes a cell cycle protein that normally inhibits G1 to S phase by recruiting histone deacetylases to inhibit transcription of genes required for S phase

Front 18

Mech of "two hit hypothesis in tumor suppressor genes

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Inherits one mutation in a tumor suppressor gene & acquires loss of a second normal copy later. 2nd hit leads to tumorigenesis.

Front 19

What is loss of heterozygosity

Back 19

Explains the 2nd hit that leads to tumor. Individ loses the remaining normal allele

Front 20

Constitutional mutations that lead to Rb

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Cytogenetically visible deletions, Cryptic deletions, Nonsense mutations, Missense

Front 21

How is test diff w/ unilat & bilat Rb?

Back 21

Bilateral – check Rb gene from blood. Unilateral – check Rb gene in blood and tumor

Front 22

Counseling Issues dealing w/ Rb

Back 22

All bilat cases are constitutional. 60-80% of bilat cases don't have FH. (however parents should have eye exam & genetic testing b/c may have benign retinomas due to Rb muts. 7% recurrence risk for parents of a bilat case. High germline mosaicism in fathers. 15% of unilat cases constitutional the rest are sporadic

Front 23

Second malignancies in Rb cases

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Mesenchymal tumors are most common childhood cancer. Osteosarcoma, fibrosarcoma, melanoma. 68% incidence of second primary malignancy to 50yo. Radiation therapy may inc risk of malignancy.

Front 24

Cause of Von Hippel Lindau

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VHL gene encodes a protein involved in the degradation of HIF-1alpha (a transcription factor that responds to hypoxia)-> highly vascularized tumors induced by artificial sensing of hypoxia. Genetic testing is standard

Front 25

Types of von Hippel Lindau

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Type 1 – truncating – low risk of pheo. Type 2 – missense and elevated risk of pheo (A: no renal cell carcinoma. B: Pheo and renal cell carcinoma. C: more pheos)

Front 26

Charac of Von Hippel Lindau

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Major cause of death is Renal cell carcinoma (clear cell). Mortality also caused by cerebellar & spinal hemangioblastomas. Often present w/ retinal angiomas. Occurrence of pheo are highly dependent on mutation location. Pancreatic cancer & endolymphatic sac tumor also occur.

Front 27

Charac of NF1

Back 27

Neurofibromin, peripheral, Chrom17, gliomas/meningiomas, cutaneous & skeletal abnormalities

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Charac of NF2

Back 28

Merlin/schwannomin, central, chrom22, schwannomas, min skin involvement, no skel abnorm

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Charac of NF3

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Schwannomatosis. No CN8 tumors

Front 30

How is NF1 diagnosed?

Back 30

Need 2/7 signs: 6 café au lait, axillary/inguinal freckle, 2 neurofibromas, 1 plexiform, >2Lisch nodules, optic glioma, skeletal dysplasia (tibia or orbit), affected 1st degree relative