The structural nature of chromosomal instability in colon cancer cells

Abstract

Biological and genetic cell heterogeneity is a landmark of most colorectal cancers and provides a frame for tumor progression as an evolutional process. Classical models have hypothesized that increased genetic instability may contribute to modulating and shaping malignant transformation. This is true for the small subset of colorectal cancers displaying microsatellite instability. For the rest of colorectal tumors, numerical and/or structural chromosomal alterations are the most prominent outcome of genetic disruption. These observations have prompted some investigators to hypothesize about the presence of chromosomal instability in these cells. To characterize chromosomal instability in cancer cells, we have analyzed genetic clonal divergence in three colorectal cancer cell lines considered to be archetypes in cancer research (HCT116, LoVo, and SW480). A dynamic setting was designed to allow the calculation of mutation rates. Comprehensive analyses at the chromosomal level revealed distinctive patterns of genetic divergence. Aneuploid SW480 cells displayed high rates of structural alterations (>100-fold) as compared with near diploid LoVo cells. Numerical alterations also occurred more frequently in SW480 cells but at low rates as compared with rearrangements in the chromosomically unstable SW480 cells. These results strengthen the role of structural instability in the generation of genetic heterogeneity in colorectal cancer.

Genetic evolution in colon cancer KM12 cells and metastatic derivates

“…33 When we compared our results to those published in the same CRC cell lines using SKY, 15,27,28 we obtained the same results using both multicolor karyotyping techniques. By comparing karyotypes of these cell lines previously analyzed by G banding carried out in our laboratory, 9,24 we confirmed that M-FISH techniques allow easy characterization of clones, avoiding misidentifications of chromosome markers and allowing us to follow them along clone generations or in vitro culture passages.…”

“…To measure the rate of instability of each cell line, which is also shown in Table II, we calculated the maxr of instability. 9 This rate takes into account only nonclonal alterations and assumes that they took place in the last generation (maxr ϭ number of nonclonal alterations/number of cells). This assessment is an indicator of genetic instability irrespective of the viability of cells showing novel genetic alterations that may or may not be transmitted to further generations.…”

“…These cell lines display the common CIN pathway, as previously described. 8,9,37 They show a near-triploid modal chromosome number with many chromosomal alterations and significant CIN rates. They are stable at the microsatellite level.…”

“…;p12) [28],Ϫ12 [28],del(12)(q13) [28], Ϫ14 [28],Ϫ15 [28],Ϫ16 [28],del(18)(q12) [28],der (18)add (18) 65ϳ69͗3n͘,XXX,ϩdel(X)(p11.2) [15],der(3)t(X;3)(q26;q28) [15],der(3)ins(3p;12) [15],ϩdel(4)(q21) [7], ϩdel(5)(q11.2) [15],Ϫ6 [15],t(6;14)(q23;q13) [15],del(7)(p15) [15],der(8)i(8q)hsr(8)(8q24) [15], der(9)ins(9;?) [15],Ϫ13 [15],i(13)(q10) [15],Ϫ14 [13],ϩ15 [15],der (17) [9]/idem,der(4)t(4;8)(q11;q11),der(9)t(9;11)(p11;q11),del(11)(q11), der (15) 75ϳ81͗3n͘,XX,ϪX [15],ϪY [15],del(3)(q25) [3],der(3)t(2;3)(q11;p11) [15],der(5)t(5;18;Y)(p13;p11.2; q11.2) [15],ϩder(5)t(5;18;Y)(p13;p11.2;q11.2) [13],der(6)t(6;12)(p21;q13) [15],ϩder(6)t(6;12)(p21; q13) [12],ϩ7 [10],ϩ8 [14],ϩ9 [14]ϩ10 [9],der(12)t(12;14)(p13;q31) [15],ϩ13 [8],ϩ14 [10],ϩ15 [13], ϩ16 [4],ϩ17 [8],Ϫ18 [15],ϩder (19) 81ϳ86͗4n...…”

“…[3][4][5][6][7] chromosome instability has been described in some CRC cell lines, resulting in numerical changes 8 (CIN) or structural rearrangements. 9 Often, these patterns are mutually exclusive; while near-diploid karyotypes usually appear with MSI and chromosome instability, near-triploid or tetraploid cells display a high degree of CIN and are stable at the microsatellite level.…”