genetics of colorectal cancer peter lee md central ohio colon & rectal center

Download Genetics of Colorectal Cancer Peter Lee MD Central Ohio Colon & Rectal Center

Post on 18-Dec-2015

212 views

Category:

Documents

0 download

Embed Size (px)

TRANSCRIPT

  • Slide 1
  • Genetics of Colorectal Cancer Peter Lee MD Central Ohio Colon & Rectal Center
  • Slide 2
  • Overview Molecular biology of cancer Epidemiology of colorectal cancer Inherited colorectal cancers Screening implications of colorectal cancer Summary
  • Slide 3
  • Cancer is a disease of the cell cycle Carcinoma is a genetic disease but it is not necessarily inherited
  • Slide 4
  • Knudsens two hit hypothesis
  • Slide 5
  • Types of genes which may mutate to cause cancer: Oncogenes Tumor suppressor genes DNA repair genes p53
  • Slide 6
  • Oncogenes Cellular oncogene c-onc Viral oncogene v-onc Proto-oncogene, activated by mutation to c-onc
  • Slide 7
  • Proto-oncogene activation
  • Slide 8
  • Tumour suppressor genes The genes normal function is to regulate cell division. Both alleles need to be mutated or removed in order to lose the gene activity. The first mutation may be inherited or somatic. The second mutation will often be a gross event leading to loss of heterozygosity in the surrounding area.
  • Slide 9
  • Types of proto-oncogene Growth factor e.g. SIS oncogene (PDGF) G proteins e.g. ras Nuclear transcription factors e.g. MYC
  • Slide 10
  • Slide 11
  • p53 Suppress progression through the cell cycle in response to DNA damage Initiate apoptosis if the damage to the cell is severe Is a transcription factor and once activated, it represses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control
  • Slide 12
  • Transformation is a multistep process
  • Slide 13
  • Slide 14
  • DNA Mismatches Damage to nucleotides in ds-DNA Misincorporation of nucleotide Missed or added nucleotides
  • Slide 15
  • Acquired DNA Damage -C-A--T-A--G-T- M Demethylation
  • Slide 16
  • Nucleotide Misincorporation -C-A-G-C-T- -G-T-C-C-A- -C-A-G-C-T- -G-T-C-C-A- -C-A-G-C-T- -G-T-T-C-A- -C-A-G-C-T- -G-T-C-C-A- correctly copied C T substitution
  • Slide 17
  • Added Nucleotides -C-A-G-C-T- -G-T-C-C-A- -C-A-G-C-T- -G-T-C-C-A- -C-A-G-C-T- -G-T-C C-A- -C-A-G-C-T- -G-T-C-C-A- A correctly copied nucleotide added
  • Slide 18
  • Human Mismatch Repair Genes MLH1 (3p21) PMS1 (2q31-33) PMS2 (7p22) MSH2 (2p16) MSH3 (5q3) MSH6 (2p16) (=GT Binding Protein)
  • Slide 19
  • Mismatch Repair Genes Recognition and repair of mismatches Other functions Repair of branched DNA structures Repair of branched DNA structures Prevent recombination of divergent sequences Prevent recombination of divergent sequences Direct non-MMR proteins in nucleotide excision and other forms of DNA repair Direct non-MMR proteins in nucleotide excision and other forms of DNA repair
  • Slide 20
  • Other MMR Proteins DNA ligase Replication protein A Replication factor C Proliferating Cell Nuclear Antigen Exonucleases DNA polymerase
  • Slide 21
  • Defective Mismatch Repair Defects in MMR Genes and Function Microsatellite Instability Cancer development 90% of HNPCC colorectal cancers 90% of HNPCC colorectal cancers 20% of sporadic colorectal cancers 20% of sporadic colorectal cancers 30% of sporadic uterine cancers 30% of sporadic uterine cancers
  • Slide 22
  • Cancer Development Activation of Oncogenes Inactivation of Tumour Suppressor Genes Defects in DNA mismatch repair Susceptible to mutation
  • Slide 23
  • Genetics of Colorectal Cancer
  • Slide 24
  • Colorectal Cancer 11% of cancer- related deaths Tumor progression may take 10-35 years Adenomatous polyp develops into carcinoma
  • Slide 25
  • Chromosome changes in colorectal cancer Cancer karyotype Stable karyotype
  • Slide 26
  • Worldwide Statistics for Colorectal Cancer (CRC) 875,000 cases in 1996 8.5% of all new cases of cancer 8.5% of all new cases of cancer 556,000 deaths Incidence rates vary (Up to 20 fold) Highest in North America, Western Europe, Australia, New Zealand, Japan Highest in North America, Western Europe, Australia, New Zealand, Japan Lowest in India, Northern Africa Lowest in India, Northern Africa
  • Slide 27
  • Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000
  • Slide 28
  • Colorectal Cancer Statistics in the US Second overall leading cause of cancer-related deaths in the USSecond overall leading cause of cancer-related deaths in the US Estimated 130,000 new cases and 56,300 deaths in the year 2000Estimated 130,000 new cases and 56,300 deaths in the year 2000 Declining trends between 1990 and 1996Declining trends between 1990 and 1996 Incidence rate: 2.1% per year Mortality rates: 1.7% per year
  • Slide 29
  • Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996
  • Slide 30
  • Prevalence of adenomas Age 50 with any adenomas: 25-40% Lifetime risk of cancer at age 50 5% for females 5% for females 6% for males 6% for males Advanced adenomas at highest risk Advanced adenomas at highest risk
  • Slide 31
  • Risk Factors for Colorectal Cancer (CRC) Aging Personal history of CRC or adenomas High-fat, low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes
  • Slide 32
  • Risk of Colorectal Cancer (CRC) 020406080100 General population Personal history of colorectal neoplasia Inflammatory bowel disease HNPCC mutation FAP 5% 15%20% 15%40% 70%80% >95% Lifetime risk (%)
  • Slide 33
  • Familial Risk for CRC Lifetime CRC risk (%) None One 1 One 1 and two 2 One 1 age
  • Characteristics of Average Risk No well-defined threshold between sporadic and familial CRC at this time Probably safe to include individuals with: No personal risk factors or family history of CRC No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC >60 years with no other family history of CRC One 2nd or 3rd degree relative with CRC >60 years with no other family history of CRC
  • Slide 41
  • C haracteristics of Familial CRC Clustering of colon cancer cases in the family (age> 50 at diagnosis) without clear dominant pattern One close relative with CRC
  • MAP syndrome/MYH gene Multiple adenomatous polyposis (MAP) syndrome Autosomal recessive; mutations in the MYH gene Autosomal recessive; mutations in the MYH gene Median number of polyps = 55 Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Mean age of polyp diagnosis = 30-50 years Small, mildly dysplastic tubular adenomas Small, mildly dysplastic tubular adenomas Some tubulovillous, hyperplastic, serrated adenomas, microadenomas Some tubulovillous, hyperplastic, serrated adenomas, microadenomas 30% of individuals with 15-100 polyps have homozygous mutations in the MYH gene Genetic testing should be offered if >15 polyps (and APC gene testing negative)
  • Slide 67
  • Peutz-Jeghers syndrome 60 or 40 years two 2 nd degree relatives with CRC any age two 2 nd degree relatives with CRC any age * Or 5-10 yrs earlier than earliest case in family Gastroenterology: 2003;124:544-560 Colonoscopy every 5 yrs Average risk screening
  • Slide 77
  • Adenoma-Carcinoma Sequence Accumulation of Mutations DCC, MCC, p53, K-ras, APC, MSH2, MLH1, etc.
  • Slide 78
  • CRC Risk Management Age to Begin Age to Begin HNPCC or suspected HNPCC 20-25 yrs FAP or suspected FAP 10-12 yrs 1.Colonoscopy every 1-2 yrs 2.Genetic counseling; consider genetic testing 1.Colonoscopy every 1-2 yrs 2.Genetic counseling; consider genetic testing 1.Flex sig or colonoscopy every1-2 yrs 2.Genetic counseling; consider genetic testing 1.Flex sig or colonoscopy every1-2 yrs 2.Genetic counseling; consider genetic testing
  • Slide 79
  • Chemoprevention Evidence that ASA, NSAIDs, Calcium, and COX-2 inhibitors may reduce incidence of CRC by reducing # of adenomas 40-50% risk reduction for developing CRC regardless of location in colon, age, gender, and race Generally performed by RCTs in patients with prior CRC followed for recurrence of adenomas Diet, fiber, and antioxidant vitamins have not been shown by RCTs to decrease risk of recurrent adenomas COX-2is and Sulindac have been shown to reduce the number of adenomas found in FAP alone Not effective for sporadic colon CA Actually can cause regression of adenomas
  • Slide 80
  • Summary
  • Slide 81
  • Summary Risk factors for colon cancer Inherited Inherited Acquired (sporadic)-adenomatous polyp, IBD Acquired (sporadic)-adenomatous polyp, IBD Genetic basis for colon cancer Inherited (FAP, HNPCC, to be defined) Inherited (FAP, HNPCC, to be defined) Sporadic polyp-different pathways Sporadic polyp-different pathways
  • Slide 82
  • Summary Genetic counseling and testing HNPCC HNPCC FAP FAP Implications for screening/surveillance Family members Family members Other malignancies Other malignancies
  • Slide 83
  • Thank you!

Recommended

View more >