DNA damage repair in colorectal cancer

ways DNA damage can be repaired

base excision repair, homologous recombination/non-homologous end joining, mismatch repair, nucleotide excision repair

consequence of accumulation of DNA damage

increased chance of activating an oncogene/deactivating tumour suppressor genes

base excision repair

glycosylase → endonuclease → polymerase → ligase

wrong base is detected, removed, hole is filled with correct base by polymerase and gap sealed by ligase

mechanism for mismatch repair

mismatch detected, removed (exonuclease), replaced by polymerase, ligases seals gap

nucleotide exicision repair mechanism

thymine dimer detected and dna opens up (helicase) to form bubble, damaged region removed, polymerase replaces and ligase seals.

double strand break repair mechanism: homologous recombination

cell cycle phase S/G2. strand invasion, elongation, end binding, processing and ligation

honhomologus end joining mechanism

cell cycle phase G0/G1. ku70/80, dna pk artemis, end binding, end processing and apposition and ligation.

colorectal cancer polyposis disorders

mans, map, nap, ppap

MAP

autosomal recessive missense mutations in MUTYH. missense Y179C and G396D most common. cause G>T transversions when trying to do DNA repair. increased duodenal, ovarian, urinary cancer risk

MANS

autosomal recessive mutations in MBD4, increased risk of AML, melanomas, ovarian cancer

NAP

autosomal recessive nonsense mutations in NTHL1, increased C>T transitions when supposed to be DNA repair. increased risks of bladder, basal cell carcinomas

PPAP

autosomal dominant mutations in POLE and POLD1, increased risks of pancreas, ovarian, duodenum and endometrial cancers.

POLE/POLD1 essential for accurate post replication surveillance (proofread/remove mispaired bases)

lynch syndrome mutations

autosomal dominant mutations in MLH1, MSH2, MSH6, PMS2, increased risks of bowel, endometrial and ovarian cancer

mismatch repair mechanism

repair enzymes MLH1, MSH2, MSH6, PMS2 help to remove mis paired bases (single bases or multiple mismatches)

oxaliplatin MOA

platinum based compound. inserts Pt into DNA → intrastrand crosslinks

PK of oxaliplatin

absorbtion: hydrolysed to reactive intermediates (mon, di and diaquo-DACH) and oxalate

distribution: highly lipophilic (plasma and tissues)

metabolism: AGXT and GRHPR enzymes

exretion: renal and erythrocyte bound

combinations with oxaliplatin

5-FU and leucovorin (to make FOLFOX)

capecitabine (to make XELOX)

main side effect of oxaliplatin

peripheral neuropathy - pare/dysae sthesia, allodynia and muscle cramps

most common DLT

can be acute (due to chelation of Ca ions and disruption of VGNaCs) or chronic (after many rounds of chemo - apoptosis of neurons due to accumulation in dorsal root ganglia)

variants in oxaliplatin induced peripheral neuropathy

CSB (damage recognition in NER pathway)

XPF (nucleotide exicison in NER pathway)