Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia with Chromothripsis in an Old Woman

Cell karyotyping in patients with small lymphocytic lymphoma/chronic lymphocytic leukemia （SLL/CLL） is not easy to success, and small genomic lesions （〈5 Mb） are not routinely detected by this method. It is likely that a complete genomic characterization of CLL requires a combination of fluorescence in situ hybridization （FISH）, single nucleotide polymorphism （SNP） array profiling for comprehensive genome-wide analysis of acquired genomic copy number aberrations （aCNAs） and loss-of-heterozygosity （LOH） in dominant clones, and karyotyping for detection of balanced translocations, isochromosomes, and marker chromosomes. SNP array analysis can reveal chromothripsis, a phenomenon by which regions of the cancer genome are shattered and recombined to generate frequent oscillations between the lower and the higher DNA copy number states. This study provided cytogenetic findings in a CLL/SLL patient with v-myc avian myelocytomatosis viral oncogene homolog （C-MYC）-amplification by FISH, in which SNP arrays detected profound genomic upheaval due to chromothripsis that may lead to malignant transformation.

Chromothripsis:an emerging crossroad from aberrant mitosis to therapeutic opportunities

Shen Chromothripsis,a type of complex chromosomal rearrangement originally known as chromoanagenesis,has been a subject of extensive investigation due to its potential role in various diseases,particularly cancer.Chromothripsis involves the rapid acquisition of tens to hundreds of structural rearrangements within a short period,leading to complex alterations in one or a few chromosomes.This phenomenon is triggered by chromosome mis-segregation during mitosis.Errors in accurate chromosome segregation lead to formation of aberrant structural entities such as micronuclei or chromatin bridges.The association between chromothripsis and cancer has attracted significant interest,with potential implications for tumorigenesis and disease prognosis.This review aims to explore the intricate mechanisms and consequences of chromothripsis,with a specific focus on its association with mitotic perturbations.Herein,we discuss a comprehensive analysis of crucial molecular entities and pathways,exploring the intricate roles of the CIP2A–TOPBP1 complex,micronuclei formation,chromatin bridge processing,DNA damage repair,and mitotic checkpoints.Moreover,the review will highlight recent advancements in identifying potential therapeutic targets and the underlying molecular mechanisms associated with chromothripsis,paving the way for future therapeutic interventions in various diseases.

Novel patterns of cancer genome evolution

Cells usually undergo a long journey of evolution during the progression from normal to precancerous cells and finally to full-fledged cancer cells. Multiple genomic aberrations are acquired during this journey that could either act as drivers to confer significant growth advantages or act as passengers with little effect on the tumor growth. Recent advances in sequencing technology have made it feasible to decipher the evolutionary course of a cancer cell on a genome-wide level by evaluating the relative number of mutated alleles. Novel terms such as chromothripsis and chromoplexy have been introduced to describe the newly identified patterns of cancer genome evolution. These new insights have greatly expanded our understanding of the initiation and progression of cancers,which should aid in improving the efficiency of cancer management and treatment.

Cohesin complexes with a potential to link mammalian meiosis to cancer

Among multiple genes aberrantly activated in cancers,invariably,there is a group related to the capacity of cell to self-renewal.Some of these genes are related to the normal process of development,including the establishment of a germline.This group,a part of growing family of Cancer/Testis(CT)genes,now includes the meiosis specific subunits of cohesin complex.The first reports characterizing the SMC1 and RAD21 genes,encoding subunits of cohesin,were published 20 years ago;however the exact molecular mechanics of cohesin molecular machine in vivo remains rather obscure notwithstanding ample elegant experiments.The matters are complicated by the fact that the evolution of cohesin function,which is served by just two basic types of protein complexes in budding yeast,took an explosive turn in Metazoa.The recent characterization of a new set of genes encoding cohesin subunits specific for meiosis in vertebrates adds several levels of complexity to the task of structurefunction analysis of specific cohesin pathways,even more so in relation to their aberrant functionality in cancers.These three proteins,SMC1β,RAD21L and STAG3 are likely involved in a specific function in the first meiotic prophase,genetic recombination,and segregation of homologues.However,at present,it is rather challenging to pinpoint the molecular role of these proteins,particularly in synaptonemal complex or centromere function,due to the multiplicity of different cohesins in meiosis.The roles of these proteins in cancer cell physiology,upon their aberrant activation in tumors,also remain to be elucidated.Nevertheless,as the existence of Cancer/Testis cohesin complexes in tumor cells appears to be all but certain,this brings a promise of a new target for cancer therapy and/or diagnostics.