TP53 Abnormalities Are Underlying the Poor Outcome Associated with Chromothripsis in Chronic Lymphocytic Leukemia Patients with Complex Karyotype

Abstract

Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared and the prognostic value of cth was analyzed. Cth was distributed throughout the genome, with chromosomes 3, 6 and 13 being those most frequently affected. OGM detected 88.1% of the previously known copy number alterations and several additional cth-related rearrangements (median: 9, range: 3–26). Two patterns were identified: one with rearrangements clustered in the region with cth (3/9) and the other involving both chromothriptic and non-chromothriptic chromosomes (6/9). Cases with cth showed a shorter time to first treatment (TTFT) than non-cth patients (median TTFT: 2 m vs. 15 m; p = 0.013). However, when stratifying patients based on TP53 status, cth did not affect TTFT. Only TP53 maintained its significance in the multivariate analysis for TTFT, including cth and genome complexity defined by genomic microarrays (HR: 1.60; p = 0.029). Our findings suggest that TP53 abnormalities, rather than cth itself, underlie the poor prognosis observed in this subset.

Mapeo óptico del genoma: fundamentos tecnológicos y aplicaciones en neoplasias hematológicas

“…En este sentido, el empleo del OGM en la LLC permite, además de identificar las anomalías estudiadas actualmente por FISH, una mejor definición de las alteraciones citogenéticas: la descripción correcta de alteraciones estructurales, como cromosomas marcadores o material adicional de origen desconocido; la identificación de reordenamientos crípticos y la detección exacta de los puntos de rotura (por ejemplo, IGH::BCL3, grupo con especial mal pronóstico); y la identificación de dos patrones de cromotripsis (definida como la presencia de CNV con un patrón alternante de al menos 7-10 segmentos, en un brazo o cromosoma entero), dependiendo de la afectación inter-o intracromosómica. Asimismo, el OGM permite una mejor definición de la complejidad genómica y se muestra como una técnica útil en la estratificación pronóstica de los pacientes 9,13,38 .…”

“…Con la técnica de OGM es posible obtener información relacionada con estos fenómenos mucho más completa y detallada. Hasta la actualidad existen pocos estudios que hayan profundizado en el impacto clínico de estos fenómenos, debido a la reciente y progresiva implementación del OGM 17,38 . Estos son una representación de la complejidad genómica que en el futuro deberá tenerse en cuenta en los laboratorios.…”

Optical genome mapping: technical basis and applications in hematological malignancies

“…This includes accurate descriptions of structural abnormalities, such as marker chromosomes or additional material of unknown origin; the identification of cryptic rearrangements and the precise detection of breakpoints (eg, IGH::BCL3, a group with particularly poor prognosis); and the identification of 2 patterns of chromothripsis (defined as the presence of CNVs with an alternating pattern of, at least, 7 to 10 segments, on one arm or the entire chromosome), depending on inter-or intrachromosomal involvement. OGM also provides a better definition of genomic complexity and proves to be a useful technique in patient prognostic stratification 9,13,38 .…”

“…With the OGM technique, we can obtain much more comprehensive and detailed information on these phenomena. Currently, few studies have been published on the clinical impact of these phenomena due to the recent and gradual implementation of OGM 17,38 . These phenomena represent the genomic complexity that laboratories will need to consider in the future.…”

Optical Genome Mapping as an Alternative to FISH-Based Cytogenetic Assessment in Chronic Lymphocytic Leukemia

“…Optical genome mapping (OGM) is a novel non-sequencing-based technique for highresolution genome-wide SV detection, and its use as an alternative to classical cytogenetic testing has been explored for various types of hematological malignancies [11][12][13][14][15][16][17]. Altogether, these studies have shown very high concordance between OGM and classical techniques, and for CLL specifically recent studies demonstrated the use of OGM as a powerful tool to assess genomic complexity [18,19]. OGM is based on the imaging of ultralong DNA molecules (average N50 of >240 kb) that are fluorescently labeled on a 6-mer single-stranded DNA motif that occurs on average 15 times per 100 kb in the human genome.…”