T2 - Neoplasia 6 - Cancer Genetics Ii

Front 1

talk about the style (recessive/dominant) inheritance of tumor suppressor genes -

also, what disease should you immediately associate with at p53 mutation?

who should you suspect of having messed up cancer genes?

Back 1

tumor suppressors exhibit "recessive" characteristics, in that you need "two hits" for the cancer phenotype to become evident.

note that inheriting one copy of the mutated gene = a DOMINANT inheritance pattern of cancer risk - you have a 50% chance of getting the messed up single gene from your parents. kind of confusing.


Li Fraoumini Syndrome = p53 mutation

suspect messed up genes in EARLY ONSET cancers, BILATERAL cancers, RARE cancers, strong FAMILY HISTORY,

Front 2

when do you test for genetic susceptibility for cancer?

how much breast/ovarian cancer is inherited?

Back 2

when family/personal history warrants it, when the test can be interpreted, and when the results will affect the management of the patient OR the patient's family.

most breast/ovarian cancer is SPORADIC, only 5-10% are due to a discrete mendelian inherited trait - another 10-15% are 'familial clusters'

Front 3

BRCA1 and BCRA2 - what kinds of genes are they? details - what populations are at risk? what else does this population have?

Back 3

these are tumor suppressors, involved in DNA repair (like ATM and HNPCC) located on chromosomes 13 and 17, respectively. Very big genes, AUTOSOMAL DOMINANT pattern of inheritance (50% chance of passing on the gene to kids). 50-85% risk of cancer with BRCA mutatations, prostate cancer risk in men for BRCA2 (and 6% breast cancer risk)

ashkanazi jews are at much higher risk - 1 in 40 carries the gene.

ashkenazis are more at risk for APC gene mutations, but not the kind that causes FAP - just more likely to get colorectal cancer

NOTE - DON'T TEST CHILDREN - it's not going to kill them as kids, wait 'till it makes sense

Front 4

when asking about breast cancer risk factors, what are interesting questions?

who do you test first in a family?

Back 4

age of first period - earlier = higher risk. generally, more time spent in reproductive age = higher risk. having kids LOWERS the risk - later pregnancy = HIGHER risk, because you spent longer without having kids.

you test the person with cancer first - more informative for other families.

there's a gail/claus model. claus model focuses in more depth on family history (it's the only risk factor considered).

Front 5

what are the genetic risks of melanoma? what are the red flags, and what does a mutation mean in terms of risk?

Back 5

p16. suspiscious of melanoma + pancreatic cancer.

CDKn2a = tumor suppressor

CDK4 = proto-oncogene.

Red flags -multiple melanomas in one person, multiple in the family, history of related pancreatic cancer.

a mutation in CDKn2a (ts) and cdk4 (po) confer a 70% lifetime risk of developing melanoma. NOTE - kids are screened at age 10, as they can get sick

Front 6

what's ataxia telangiaectasia? symptoms and mutations? lab findings?

Back 6

see progressing clumsy walk, weird eye findings (vessels), slurred speech and repeated infections. weird looking to the side

Mutated DNA repair gene.

NO ATM protein found on labs. high alpha fetoprotein. 7:14 translocation.

some increased risk for blood cancers, worsening symptoms, death in the 20's.

Front 7

if you see a pedigree that's riddled with random awful cancers, what disease and mutation should we think of?

Back 7

Li Fraumeni syndrome - this is the one that's associated with the p53 mutation (tumor suppressor). Recall that p53 has to be mutated in most caners - so inheriting a bad copy = very very bad.

test kids for sure.

Front 8

what if you see someone with mucocutaneous stigmata, thick soles of the feet, and big heads? Gene involved?

Back 8

macrocephaly + thick feet + mucocutaneous stigmata = Cowden Syndrome.

TS called PTEN mutation. random tumors include breast, thyroid, endometrial.

Front 9

what's multiple endocrine neoplasia?


what do you think of you see a lot of renal cancers in one family? other symptoms? details?

Back 9

see early development of medullary thyroid cancer, tall stature, and weird bumps on the tongue. caused by several completely different mutations.

see really weird parathyroid tumors/medullary thyroid tumors,

with MEN1 (TS), likely to get parathyroid tumors. with RET (oncogene) mutation, likely to get the thyroid medullary tumor.

Von-Hippel Lindau syndrome - dominant pattern of inheritance. see hemangioblastomas of CNS. renal cysts, etc. VHL gene = TS.
Sack tumors - endolymphatic sack tumors.

Front 10

what about hyperpigmented macoules all over the face and lots of intestinal polyps?

what about increased head circumference, jaw cysts, coarse facial features, basal cell carcinomas all over?

Back 10

peutz jegher's syndrome! stk111 gene mutations, lots of hamartomas, hyperpigmentation in mouth/eyes/nostrils,


basal cell nevous syndrome = jaw cysts, macrocephaly, bossing of forehead, etc. PTCH gene.

Front 11

what is knudson's two hit theory and vogelsteins' model of colon carcinoma?

Back 11

knudson's two hit theory - takes two hits to loose a tumor suppressor's function, sometimes you're already born with one hit.

vogelstein's model - first have normal colon cells, then some increased growth which given an opportunity for adenomas to form, then later get 'late adeonomas,' then a carcinoma, and then metastasis.

note K ras is an early mutation, that APC (tumor suppressor kills beta catenin which turns off cell cycle growth) mut may lead to first increased cell growth, that DCC (deleted in colon cancer = eCadherin = tumor suporessor) may be the oncogene involved in making a "late" adenoma, that p53 gets you to a carcinoma, and that loss of NM23 gets to metastasis (it's an oncogene that can turn OFF p53 completely).