{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T14:50:37Z","timestamp":1791125437125,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T00:00:00Z","timestamp":1414800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cancers are characterized by genomic instability, and the resulting intraclonal diversity is a prerequisite for tumor evolution. Therefore, metrics of tumor heterogeneity may prove to be clinically meaningful. Intraclonal heterogeneity in follicular lymphoma (FL) is apparent from studies of somatic hypermutation (SHM) caused by activation-induced deaminase (AID) in IGH. Aberrant SHM (aSHM), defined as AID activity outside of the IG loci, predominantly targets noncoding regions causing numerous \u201cpassenger\u201d mutations, but it has the potential to generate rare significant \u201cdriver\u201d mutations. The quantitative relationship between SHM and aSHM has not been defined. To measure SHM and aSHM, ultradeep sequencing (&amp;gt;20,000-fold coverage) was performed on IGH (\u223c1650 nt) and nine other noncoding regions potentially targeted by AID (combined 9411 nt), including the 5\u2032 untranslated region of BCL2. Single-nucleotide variants (SNVs) were found in 12\/12 FL specimens (median 136 SHMs and 53 aSHMs). The aSHM SNVs were associated with AID motifs (p &amp;lt; 0.0001). The number of SNVs at BCL2 varied widely among specimens and correlated with the number of SNVs at eight other potential aSHM sites. In contrast, SHM at IGH was not predictive of aSHM. Tumor heterogeneity is apparent from SNVs at low variant allele frequencies; the relative number of SNVs with variable allele frequency &amp;lt; 5% varied with clinical grade, indicating that tumor heterogeneity based on aSHM reflects a clinically meaningful parameter. These data suggest that genome-wide aSHM may be estimated from aSHM of BCL2 but not SHM of IGH. The results demonstrate a practical approach to the quantification of intratumoral genetic heterogeneity for clinical specimens.<\/jats:p>","DOI":"10.4049\/jimmunol.1401699","type":"journal-article","created":{"date-parts":[[2014,10,13]],"date-time":"2014-10-13T22:16:22Z","timestamp":1413238582000},"page":"4888-4894","source":"Crossref","is-referenced-by-count":13,"title":["Intraclonal Diversity in Follicular Lymphoma Analyzed by Quantitative Ultradeep Sequencing of Noncoding Regions"],"prefix":"10.1093","volume":"193","author":[{"given":"Janice M","family":"Spence","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Rochester Medical Center , Rochester NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Abumoussa","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Rochester , Rochester NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P","family":"Spence","sequence":"additional","affiliation":[{"name":"NGS Tech , Webster, NY 14580"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5584-584X","authenticated-orcid":false,"given":"W Richard","family":"Burack","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Rochester Medical Center , Rochester NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,11,15]]},"reference":[{"key":"2025030707470093900_r1","article-title":"Transformed lymphoma: a therapeutic challenge","author":"Casulo","year":"2014","journal-title":"Blood."},{"key":"2025030707470093900_r2","first-page":"532","article-title":"The incidence, natural history, biology, and treatment of transformed lymphomas","volume-title":"Hematology Am. 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