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BIOL 310 - Ch 23 Lecture Notes

  • what is cancer?

    • cancer is complex & environmental, it is genetic disease; the progress made in understanding tumorigenesis in large part is owing to the discovery of the genes that when mutated lead to cancer

  • cancer origins

    • point mutations (leads to frame shifts)

    • chromosome

      • translocation of c-ABL on chromosome nine to chromosome 22 (BCR gene to chromosome 22)

        • BCR c-ABL gene protein loses function

        • associated with chronic myelogenous leukemia

    • duplications

    • amplifications

      • only in cancer cells

      • 5 to 100-fold increase in copy#

      • enhance proliferation; extra repeats of certain part of the chromosome

  • exogenous sequences (outside in)

  • cancer is a cell cycle breakdown

    • they are not arrested at either the G1 or G2 checkpoint — replicate

    • cyclins

    • cyclin-dependent kinases (CDKs)

    • problem

      • deregulated cyclin/CDK production

    • result — new cell “clone”

  • clonal expansions

    • healthy cell divides — one daughter cell has a mutation and will divide uncontrollably for multiple generations (expansion in number of mutations present)

  • common culprits: oncogenes

    • common cancer-causing genes (genes that are supposed to be off)

      • gene activation

      • cell-cycle regulation

  • common culprit: tumor suppressor

    • gene inactivation

      • familial cancer syndromes

    • loss of heterozygote

      • two-hit hypothesis

  • retinoblastoma example

    • autosomal dominant

    • RB1 gene on chromosome 13 — inherit two faulty alleles or one healthy and one mutant allele

    • prototype for 2-hit

    • Alfred Knudson

  • retinoblastoma: loss of allele

  • DNA repair genes

    • loss of function mutations

    • differ from TSG

      • indirectly involved in growth, inhibition or differentiation

    • inactivation

      • increased standing mutation load — individuals will have more mutation in cells; proto-oncogenes & TSG

    • mutation accumulation

      • cancer progression is accelerated

      • progression of “pathways”

  • pathway to androgen-independent prostate cancer

  • pathways to primary and secondary glioblastomas

  • cancer cytogenetic definitions

    • clone — abnormal cells that are cytogenetically identical to each other

    • sub-clone — cells that contain the primary & additional secondary aberrations, related to the main-line clone

    • clonal evolution — the process whereby tumor cells accumulate additional mutations over time; drives the neoplastic process, drug resistance, metastatic process

    • primary aberration — cytogenetic aberration that is either by itself or common to all cells examined, even in the presence of other aberrations

    • secondary aberration — found usually in a subset of cells, indicative of clonal evolution and disease progression

  • 46, XY, t(9;22) (q34; q11.2)

  • 46, XX, inv(3) (q21q26), del(6)(q21q27)

  • risk and prognosis based on cytogenetic data

    • risk

      • mutation presence vs cancer incidence

    • prognosis

      • normal karyotype vs abnormal karyotype

      • percentage of normal vs abnormal cells

      • exact aberrations present, ploidy of cells

      • complexity of karyotype in main clone

      • presence and extent of clonal evolution

      • finding of double minutes/HSRs which indicate gene amplification

      • abnormal karyotype finding after successive normal studies

  • aberrations vs prognosis

    • Kaplan-Meier survival curves

  • prostate cancer

    • PSA testing is standard

    • moving beyond PSA

    • bone scan index

      • BSI > 1.0 — predictive pattern, greater mortality