PMC8190481_01
Allelic imbalance of chromosome 1q was observed in three of the four mantle cell lymphoma cases: in two at relapse in the central nervous system (patient 1 and 3, cerebrospinal fluid (CSF)) and one at diagnosis (patient 2). Each individual plot displays the allele frequencies of heterozygous variants (VAF) on chromosome 1 and significant deviation, or imbalance, from normal disomy. In all three cases, the aberration spanned almost 100 megabases distal to the centromere, and thus the majority of the q-arm. Sequencing of patient 2 CSF relapse material failed and thus could not be evaluated (*). All three evident allelic imbalances on the q-arm were significantly different from the p-arm (***, Wilcoxon rank-sum test:p <= 10-4, Kolmogorov-Smirnov test of equal distributions: p <= 10-4).
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A high burden deletion (~80%) was found at relapse on chromosome 1q (approximately 95 Mb, Fig. 1, patient 1 panel D, and Fig. 2) by whole-exome sequencing (WES). In addition, a distal 1q deletion of approximately 100 Mb was detected utilizing VAF and read depth ratio analyses of tumor-control pair (Fig. 1, patient 2, panel A), with an estimated cell fraction of 25-30%. This patient also displayed a large allelic imbalance (Fig. 1, patient 3, panel C) of 95-100 Mb at the same location as patients 1 and 2 (Fig. 2), however showing evidence of a chromosome copy-gain (Fig. 3, patient 3).
The size of the allelic imbalance on chromosome 1q was found to be approximately 100 megabases distal to the centromere across the three patients with apparent copy-alterations (the gradient marks the approximate starting point of the lesion of the four patients, as it is not possible to conclude the exact position from the whole-exome sequencing resolution).
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In addition, a distal 1q deletion of approximately 100 Mb was detected utilizing VAF and read depth ratio analyses of tumor-control pair (Fig. 1, patient 2, panel A), with an estimated cell fraction of 25-30%.
Coverage of the chromosome 1 q-arm region afflicted by allelic imbalance relative to the unaffected p-arm. Chromosome 1q of patient (pt.) 1 and 2 were evident of a copy-loss (A, dark gray), while a copy-gain was indicated for patient 3 (dark gray). All read depth ratios were normalized to that of the respective paired control. Samples without statistically significant allelic imbalance on the q-arm (white) were in close agreement with the paired control samples. BM: bone marrow, LN: lymph node, CSF: cerebrospinal fluid, PF: pleura fluid, DT: Dorsal tumor. The chromosome 1q imbalance observed in patient 1, 2 and, 3 were supported by qPCR (TaqMan Copy Number Assay) targeting the ABL2 gene (chromosome 1q25.2) and the reference gene TERT (chromosome 5p15.33).
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This patient also displayed a large allelic imbalance (Fig. 1, patient 3, panel C) of 95-100 Mb at the same location as patients 1 and 2 (Fig. 2), however showing evidence of a chromosome copy-gain (Fig. 3, patient 3).
Fundoscopy showing infiltration of malignant cells in corpus vitreum at relapse (left and right eye). Patient 4 experienced a CNS relapse without cerebrospinal clonal B cells. The patient was still alive after 60 months, and the malignant cells did not show any aberrations on chromosome 1 in contrast to the other cases.
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Assessment of the infiltration of corpus vitreum by fundoscopy confirmed the CNS relapse (Fig. 4), while no malignant cells were present in the CSF.