Abstract
AbstractInterpretation of allelic copy measurements at polymorphic markers in cancer samples presents distinctive challenges and opportunities. Due to frequent gross chromosomal alterations occurring in cancer (aneuploidy), many genomic regions are present at homologous-allele imbalance. Within such regions, the unequal contribution of alleles at heterozygous markers allows for direct phasing of the haplotype derived from each individual parent. In addition, genome-wide estimates of homologue specific copy- ratios (HSCRs) are important for interpretation of the cancer genome in terms of fixed integral copy-numbers. We describe HAPSEG, a probabilistic method to interpret bi- allelic marker data in cancer samples. HAPSEG operates by partitioning the genome into segments of distinct copy number and modeling the four distinct genotypes in each segment. We describe general methods for fitting these models to data which are suit- able for both SNP microarrays and massively parallel sequencing data. In addition, we demonstrate a specially tailored error-model for interpretation of systematic variations arising in microarray platforms. The ability to directly determine haplotypes from cancer samples represents an opportunity to expand reference panels of phased chromosomes, which may have general interest in various population genetic applications. In addition, this property may be exploited to interrogate the relationship between germline risk and cancer phenotype with greater sensitivity than is possible using unphased genotype. Finally, we exploit the statistical dependency of phased genotypes to enable the fitting of more elaborate sample-level error-model parameters, allowing more accurate estimation of HSCRs in cancer samples.
Highlights
The genomes of human cancer cells frequently harbor copy-number alterations, ranging from focal gain and loss of small regions to widespread chromosomal aneuploidy [1], [2], in many cases exacerbated by DNA ploidy increases followed by predominant attrition of the fixed DNA in the evolving somatic clone [3]
Estimation of the precise contribution of each homologue in a DNA sample obtained from cancer tissue is crucial to understand the genetic alterations occurring in the cancer cells
Such estimation requires the identification and interpretation of alterations in the genetic sequence of each homologue, such as they appear in the cancer sample, which contains a mixture of DNA derived from both cancerous and normal cells
Summary
The genomes of human cancer cells frequently harbor copy-number alterations, ranging from focal gain and loss of small regions to widespread chromosomal aneuploidy [1], [2], in many cases exacerbated by DNA ploidy increases followed by predominant attrition of the fixed DNA in the evolving somatic clone [3]. Detection of genomic regions with fixed somatic loss of heterozygosity - (LOH) helps identify recessively inactivated tumor suppressors, carrying mutations on the retained allele [6]. Human genomes are normally diploid, with one haploid genome inherited from each parent ( tetraploid cells are involved in physiological processes [10].) As a result of widespread chromosomal aneuploidy, many genomic regions are in homologos-allele imbalance, with the two homologues fixed at unequal copy-numbers within the somatic clone [3]. For SNP microarrays, probes for each SNP allele are calibrated using diploid control samples [13], making genotype calls unreliable in aneuploid samples [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
