TY - JOUR
T1 - Pan cancer patterns of allelic imbalance from chromosomal alterations in 33 tumor types
AU - Sivakumar, Smruthy
AU - Lucas, F. Anthony San
AU - Yasminka A Jakubek, A Jakubek
AU - Ozcan, Zuhal
AU - Fowler, Jerry
AU - Scheet, Paul
N1 - Funding Information:
This work was supported in part by NIH (Grant Nos. R01 HG005855 and R01 CA181244) and P30 CA016672, Cancer Prevention and Research Institute of Texas (CPRIT) (Grant No. RP160668), and the Pauline Altman-Goldstein Foundation Discovery Fellowship (MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences) to S.S.
Publisher Copyright:
© 2020 The Author(s).
PY - 2021
Y1 - 2021
N2 - Somatic copy number alterations (SCNAs) serve as hallmarks of tumorigenesis and often result in deviations from one-to-one allelic ratios at heterozygous loci, leading to allelic imbalance (AI). The Cancer Genome Atlas (TCGA) reports SCNAs identified using a circular binary segmentation algorithm, providing segment mean copy number estimates from single-nucleotide polymorphism DNA microarray total intensities (log R ratio), but not allele-specific intensities ("B allele"frequencies) that inform of AI. Our approach provides more sensitive identification of SCNAs by modeling the "B allele"frequencies jointly, thereby bolstering the catalog of chromosomal alterations in this widely utilized resource. Here we present AI summaries for all 33 tumor sites in TCGA, including those induced by SCNAs and copyneutral loss-of-heterozygosity (cnLOH). We identified AI in 94% of the tumors, higher than in previous reports. Recurrent events included deletions of 17p, 9q, 3p, amplifications of 8q, 1q, 7p, as well as mixed event types on 8p and 13q. We also observed both site-specific and pan-cancer (spanning 17p) cnLOH, patterns which have not been comprehensively characterized. The identification of such cnLOH events elucidates tumor suppressors and multi-hit pathways to carcinogenesis. We also contrast the landscapes inferred from AI- and total intensity-derived SCNAs and propose an automated procedure to improve and adjust SCNAs in TCGA for cases where high levels of aneuploidy obscured baseline intensity identification. Our findings support the exploration of additional methods for robust automated inference procedures and to aid empirical discoveries across TCGA.
AB - Somatic copy number alterations (SCNAs) serve as hallmarks of tumorigenesis and often result in deviations from one-to-one allelic ratios at heterozygous loci, leading to allelic imbalance (AI). The Cancer Genome Atlas (TCGA) reports SCNAs identified using a circular binary segmentation algorithm, providing segment mean copy number estimates from single-nucleotide polymorphism DNA microarray total intensities (log R ratio), but not allele-specific intensities ("B allele"frequencies) that inform of AI. Our approach provides more sensitive identification of SCNAs by modeling the "B allele"frequencies jointly, thereby bolstering the catalog of chromosomal alterations in this widely utilized resource. Here we present AI summaries for all 33 tumor sites in TCGA, including those induced by SCNAs and copyneutral loss-of-heterozygosity (cnLOH). We identified AI in 94% of the tumors, higher than in previous reports. Recurrent events included deletions of 17p, 9q, 3p, amplifications of 8q, 1q, 7p, as well as mixed event types on 8p and 13q. We also observed both site-specific and pan-cancer (spanning 17p) cnLOH, patterns which have not been comprehensively characterized. The identification of such cnLOH events elucidates tumor suppressors and multi-hit pathways to carcinogenesis. We also contrast the landscapes inferred from AI- and total intensity-derived SCNAs and propose an automated procedure to improve and adjust SCNAs in TCGA for cases where high levels of aneuploidy obscured baseline intensity identification. Our findings support the exploration of additional methods for robust automated inference procedures and to aid empirical discoveries across TCGA.
KW - Allelic imbalance
KW - Cancer aneuploidy
KW - Copy number alterations
KW - Genomic instability
UR - http://www.scopus.com/inward/record.url?scp=85101530585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101530585&partnerID=8YFLogxK
U2 - 10.1093/GENETICS/IYAA021
DO - 10.1093/GENETICS/IYAA021
M3 - Article
C2 - 33683368
AN - SCOPUS:85101530585
SN - 0016-6731
VL - 217
JO - Genetics
JF - Genetics
IS - 1
M1 - iyaa021
ER -