Hereditary cancer and faulty DND repair syndromes Flashcards
what types of neoplasms are associated with lynch syndrrome?
colorectal cancer
endometrial cancer
ovarian cancer
lynch syndome = hereditary non-polyposis colorectal cancer
what genes are associated with lynch syndrome?
MSH2
MLH1
MSH6
PMS2
what is the mechanism for lynch syndrome?
autosomal domonant INACTIVATING mutation of a tumor suppressor genes (RESPONSIBLE FOR MISMATCH REPAIR) — leads to microsatellite insitibility of DNA
deletion of the remaining normal allele (second hit) leads to loss of heterozygosity and malignant transformation
what neoplasms are associated with familial adenomatous polyposis?
colorectal cancer
desmoids and osteomas
brain tumors
what gene is associated with familial adenomatous polyposis?
APC
what is the mechanims for familial adenomatous polyposis?
inactivating mutation of tumor supressor gene along with second hit loss of heterozygosity and malignant transformation
what types of neoplasms are associated with von-hippel lindau syndrome?
hemangioblastomas
clear cell renal cell carcinoma
pheochromocytoma
what causes von hippel lindau ?
mutation of VHL gene , loss of tumor supressor + deletion of remaining allele and loss of heterozygosity leads to malignant transformation
what neoplasms are associated with li-fraumeni syndome?
sarcomas breast cancer brain tumors adrenocortical carcinoma leukemia
what gene is fucked up in le-fraumeni sysndome?
TP53 – inactivating mutation of a tumor supressor gene ==> second hit causes malignant trandformation due to loss of remainng normal allele
what gene is fucked up in multiple endocine neoplasea 1? WHat is the mechanism for development of parathyroid adenomas, pituitary adenomas, and pancreatic adenomas?
MEN1
inactivating mutation of a tumor supressor gene ==> second hit causes malignant trandformation due to loss of remainng normal allele
what is fucked up in multiple endocrine neoplasea 2?
what is the mechanism?
RET - activating (gain of function) mutation in proto-oncogene leading to continuous stimulation of cell devisions
leads to medulary thryroid cancer (solitary thryoid nodule) hyperparathyroidism and pheochromacytoma
what gene?
hemangioblastomas
clear cell renal cell carcinoma
pheochromocytoma
VHL
von-hippel lindau
what gene? What syndrome? sarcomas breast cancer brain tumors adrenocortical carcinoma leukemia
TP53
li-fraumeni
what gene? what syndrome?
colorectal cancer
desmoids and osteomas
brain tumors
APC
familial adenomatous polyposis
what gene? what syndrome?
colorectal cancer at an early age that most commonly affects the proximal bowel
endometrial cancer
ovarian cancer
MSH2
MLH1
MSH6
PMS2
lynch syndrome
what does elevated CA-125 indicate?
ovarian cancer
what is fucked up in ataxia-telangiectasia?
ATM gene mutationn leads to inactivation of tumor supressor p53, reuslting is disruption of the non-homologous end joining repair mechanism
this mechanism is particularly important in repairing damage due to ionizing radiation
what is most likely associated neoplasm for ataxia-telangiectasia?
primary CNS lymphoma and leukemia
what disorder is characterized by failure to repair cyclobutane pyrimidine dimers?
xeroderma pigmentosum
defective nucleotide excision repair mechanisms
autosomal recessive
what are the clinical symptoms of xeroderma pigmentosum?
photosensitivity, increased pigmentation, xerosis (abnormal skin dryness).
what are pts with xeroderma pigmentosum at increased risk for?
Corneal ulcers and cutaneous malignancies:
squamous cell carcinoma
basal cell carcinoma
melanoma
treatment is with complete avoidance of sunlight
pt presents with
short stature
rash from sun exposure
predisposed to lymphoproliferative and gastrointestinal malignancies
what do they have?Bloom syndrome
may also have café-au-lait spot or tangelectasias
what’s the cause of bloom syndome?
lack of BLM helicase enzyme due to defective RecQL3 gene - impaired homologous recombination
BLM helicase is normally involved in repairing double-strand breaks
requires a sister chromatid to use as a template
therefore must occur after S phase of cell cycle
what type of repair mechanism is used to fix when the bond between the sugar backbone and the nucleotide (glycosidic bond) has been severed?
base excision repair (BER)
The BER pathway starts off with a DNA glycosylase recognizing and removing the damaged base. An apurinic/apyrimidinic endonuclease cleaves the backbone, removing the remaining sugar fragment. The gap is then filled by the cell’s DNA replication machinery - DNA polymerase and ligase.
what type of repair mechanism corrects damage done from UV-B light?
Nucleotide Excision Repair - removes thymidine dimers
what gene mutation occurs in hereditary retinoblastoma?
Rb defect - loss of inhibition of E2F permits S phase gene transcription and malignant transformation
N-myc may also be involved
