Impact of genetic dynamics and single-cell heterogeneity on development of nonstandard personalized medicine strategies for cancer.

Cancers are heterogeneous and genetically unstable. Current practice of personalized medicine tailors therapy to heterogeneity between cancers of the same organ type. However, it does not yet systematically address heterogeneity at the single-cell level within a single individual's cancer or the dynamic nature of cancer due to genetic and epigenetic change as well as transient functional changes. We have developed a mathematical model of personalized cancer therapy incorporating genetic evolutionary dynamics and single-cell heterogeneity, and have examined simulated clinical outcomes. Analyses of an illustrative case and a virtual clinical trial of over 3 million evaluable "patients" demonstrate that augmented (and sometimes counterintuitive) nonstandard personalized medicine strategies may lead to superior patient outcomes compared with the current personalized medicine approach. Current personalized medicine matches therapy to a tumor molecular profile at diagnosis and at tumor relapse or progression, generally focusing on the average, static, and current properties of the sample. Nonstandard strategies also consider minor subclones, dynamics, and predicted future tumor states. Our methods allow systematic study and evaluation of nonstandard personalized medicine strategies. These findings may, in turn, suggest global adjustments and enhancements to translational oncology research paradigms.

Emerging paradigms in cancer genetics: some important findings from high-density single nucleotide polymorphism array studies.

High-density single nucleotide polymorphism (SNP) mapping arrays have identified chromosomal features whose importance to cancer predisposition and progression is not yet clearly defined. Of interest is that the genomes of normal somatic cells (reflecting the combined parental germ-line contributions) often contain long homozygous stretches. These chromosomal segments may be explained by the common ancestry of the individual's parents and thus may also be called autozygous. Several studies link consanguinity to higher rates of cancer, suggesting that autozygosity (a genomic consequence of consanguinity) may be a factor in cancer predisposition. SNP array analysis has also identified chromosomal regions of somatic uniparental disomy (UPD) in cancer genomes. These are chromosomal segments characterized by loss of heterozygosity (LOH) and a normal copy number (two) but which are not autozygous in the germ-line or normal somatic cell genome. In this review, we will also discuss a model [cancer gene activity model (CGAM)] that may explain how autozygosity influences cancer predisposition. CGAM can also explain how the occurrence of certain chromosomal aberrations (copy number gain, LOH, and somatic UPDs) during carcinogenesis may be dependent on the germ-line genotypes of important cancer-related genes (oncogenes and tumor suppressors) found in those chromosomal regions.

The signatures of autozygosity among patients with colorectal cancer.

Previous studies have shown that among populations with a high rate of consanguinity, there is a significant increase in the prevalence of cancer. Single nucleotide polymorphism (SNP) array data (Affymetrix, 50K XbaI) analysis revealed long regions of homozygosity in genomic DNAs taken from tumor and matched normal tissues of colorectal cancer (CRC) patients. The presence of these regions in the genome may indicate levels of consanguinity in the individual's family lineage. We refer to these autozygous regions as identity-by-descent (IBD) segments. In this study, we compared IBD segments in 74 mostly Caucasian CRC patients (mean age of 66 years) to two control data sets: (a) 146 Caucasian individuals (mean age of 80 years) who participated in an age-related macular degeneration (AMD) study and (b) 118 cancer-free Caucasian individuals from the Framingham Heart Study (mean age of 67 years). Our results show that the percentage of CRC patients with IBD segments (>or=4 Mb length and 50 SNPs probed) in the genome is at least twice as high as the AMD or Framingham control groups. Also, the average length of these IBD regions in the CRC patients is more than twice the length of the two control data sets. Compared with control groups, IBD segments are found to be more common among individuals of Jewish background. We believe that these IBD segments within CRC patients are likely to harbor important CRC-related genes with low-penetrance SNPs and/or mutations, and, indeed, two recently identified CRC predisposition SNPs in the 8q24 region were confirmed to be homozygous in one particular patient carrying an IBD segment covering the region.