S89: Cancer Genetics Learning Objectives 1) Understand that for most cancers, the inheritance is sporadic, but be able to recognize familial and hereditary cancers. Hereditary cancer accounts for a small # of cancer cases. 2) For a cell to become a cancer, multiple mutations need to occur. 3) Know the following terms: oncogene, tumor suppressor gene, caretaker tumor suppressor gene, gatekeeper tumor suppressor gene. 4) Explain what's meant by the Two-Hit Hypothesis. 5) Be able to recognize and name the known common cancer genetic syndroms, their genetic basis, and clues in family history that would lead you to suspect a genetic form of cancer. 1) Understand that for most cancers, the inheritance is sporadic, but be able to recognize familial and hereditary cancers. Hereditary cancer accounts for a small # of cancer cases. - Cancer!- Cancer= the uncontrolled growth of a given cell type such that: !- cell division cont. unchecked!- cell death rates are reduced!- cells can grow and invade other tissues where that cell type isn't usually located (metastasize)!- cells interfere w/normal body function, limit normal cell functioning and crowd out normal cells (tumor burden)!- How common is cancer - 1/3 of pop'n will experience cancer in their lives!- accounts for 20% of deaths in all developed countries!- most common: men= prostate, colon, lung. women= breast, colon, lung!- Early diagnosis improves outcome - w/o treatment, most cancer --> death!- many studies show benefit of early detection and early treatment of cancer, reason for surveillance!- genetic testing= means for early diagnosis!- Sporadic vs. Familial vs. Hereditary Causes - Sporadic: freq. the only person in the fam w/cancer, no germline mut that would increase the risk for cancer!- Familial: Fam Hx shows many primary and secondary relatives w/cancer, but no evidence of a cancer syndrome or germline mut. There's an increased risk of cancer to a person w/this fam Hx.!- Hereditary: There's a germline mut inherited in an autosomal dom. way that significantly increases lifetime risk of cancer. 2) For a cell to become a cancer, multiple mutations need to occur. - Multistep cancer process - this is how sporadic cancers occur!- cell acquires a critical mutation --> leads to additional muts --> cell now has ability to grow, proliferate, and invade unchecked - there's a sequentional nature of mutations in cancer!- diff. tumors have diff. mutation profiles 3) Know the following terms: oncogene, tumor suppressor gene, caretaker tumor suppressor gene, gatekeeper tumor suppressor gene.- Oncogene - muts in genes that are NORMAL cellular protein coding genes that promote cell survival or limit cell death!ex. genes in signaling pathways: RET, RAS!ex. inhibitors of cell death: FAS, BLC2!- typically cause cancer by a gain of function mutation!- Tumor Suppressor Genes!- Gatekeepers: control cell growth by regulating checkpoints thru cell cycle or by promoting programmed cell death!- Caretakers: guardian's of the cell's genome, they correct normal day to day error that occur in genome!- Tumor suppressors genes typ. cause cancer by loss of function mutation!- Sporadic Cancers!- Cancers can develop from muts that occur in a SINGLE CELL in an individual!- that cell and its progeny may need to accum. many muts over many cell divisions over many yrs!- typ. occur later in life!- ex. Colon cancer in an 80 y/o w/no fam Hx of disease!- Familial Cancer!- May be yet to be identified genomic variants in some fams that lead to increased cancer risk!- Fam Hx may have increased #s of cancers of single or many types!- Patterns don't fit known cancer syndromes or genetic testing doesn't show a specfic cancer gene!- imp. area for research, may reveal unknown genetic or envi susceptibilities! 4) Explain what's meant by the Two-Hit Hypothesis. - Two Hits to Cancer!- Already have 1 mut. in zygote, get a 2nd somatic mutation in retina cell (in other copy of chrom. in RB gene)!- this mut. can be ANYTHING in the Rb gene, doesn't have to be the same exact mut!- in person: we'll see 2 tumors, 2nd mut. is unique between tumor and 1st mut (germline) is same in all!- RB inherited:!- Dominant in person: need mut. in 1 copy to be at huge increased risk (parent has 1 chrom w/1 mut and only needs to pass on 1 mutation). It's dominant for the RISK for developing Retinoblastoma.!- Recessive in cell: takes 2 hits to make tumor happen!- Whereas in the sporadic cancer, you likely only see tumor in 1 spot on 1 side 5) Be able to recognize and name the known common cancer genetic syndroms, their genetic basis, and clues in family history that would lead you to suspect a genetic form of cancer. - Hereditary Cancer: Rules - Autosomal dominant!- Penetrance isn't 100%, but is very high ex. FAP risk is almost 100% for some fams!- If mut is in a tumor suppressor gene, req. a 2nd hit for cancer to start!- Freq. cell type (cancer type) specific, but may have patterns of tumors !- Tend to be bilateral in paired organs (ex. Retinoblastoma, breast cancer)!- Tend to be early onset, earlier than typical age for a given tumor!- There are 54 described hereditary cancer syndromes!- Focus today: Retinoblastoma, Colon cancer syndromes (FAP, Lynch syndrome), Li-FraumeniSyndrome, Breast cancer syndromes (BRCA1 and BRCA2)!- Retinoblastoma!- Caused by germline muts in the RB gene, but single mut. alone isn't enough to cause cancer!- A single cell that gets a 2nd mutation in RB gene needs to occur to develop a tumor!- Very early onset of tumor (ex. can be at birth)!- Tumors can be bilateral and at many sites in retina!- Later in life, affected people are at risk for osteosarcome (bone cancer)!- RB gene --> encodes a Gatekeeper that keeps control on cell cycle!- Retinoblast cells in developing retina w/2 muts in RB gene can proliferate uncontrollably and develop a tumor!- Tumor occurs earlier and in >1 site because it already has 1 mut. and only needs 1 more to go!- Colon Cancer - 2 common types of hereditary colon cancer:!- Familial Adenomatous Polyposis (FAP): muts in APC gene - Lynch Syndrome (aka HNPCC= hereditary non-poliposis colon cancer, old name)!- muts in mis-match repair genes!- FAP!- Caused by autosomal dom. muts in APC gene!- Diagnostic characteristics: !- > 100 colorectal adenomatous polyps!- < 100 polyps and relative w/FAP!- attenuated forms may have fewer polyps!- onset of polyps early in life, median age= 16 y/o !- Polyps are 1st benign and then progress to cancer!- >95% of
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