Organ Site Cancer Selection

Kuismanen et al. (41) noted that the genetic basis of organ susceptibility to malignant transformation is poorly understood in the Lynch syndrome. Given the fact that carcinogenesis in this disorder is driven by defective MMR DNA, these investigators compared instability at microsatellite sequences in the endometrium and colorectum, the two organs most commonly affected in this disorder. They analyzed patients with identified predisposing MLH1 or MSH2 MMR gene mutations for noncoding (BAT25,

BAT26, BAT40) and coding mononucleotide repeats in the MSH6, MSH3, MLH3, BAX, IGF2R, TGFfiRII, and PTEN genes, in addition to MLH1- and MSH2--linked dinu-cleotide repeats (D3S1611 and CA7). Their findings disclosed significant quantitative and qualitative differences between the two tumor types. Whereas CRCs displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF^RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernable in ECs. Instead, the pattern was more heterogeneous, with a lower proportion of unstable markers per tumor (mean 0.27 for ECs vs 0.45 for CRCs, p < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable ECs vs 9.3 bp for CRCs, p < 0.001). Among the individual putative target loci, PTEN instability was associated with ECs, and TGFftRII instability was associated with CRCs. These findings led the authors to conclude that the instability profile of EC differs from that of CRC, even though an identical genetic predisposition underlies the organ-specific differences that are crucial determinants of the Lynch syndrome tumor spectrum.

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