Clone: A group of cells that derive from a common parent cell and share its genome. 
• Malignant clone: A clone generated by the occurrence in the parent cell of a somatic mutation that alters the cell biology and function. 
• Founding or initiating clone: A malignant clone generated by a founding somatic mutation. 
• Subclone: A clone generated by the occurrence of an additional driver mutation in a cell of an already established clone. 
• Clonal architecture: Clonal composition of a neoplasm based on its clonal origin and subclonal evolution. 
• Clonal dominance: A condition in which most cells of a tissue belong to a clone. In myelodysplastic syndromes, about 85-90% of bone marrow cells are clonally derived. 
• Subclonal evolution or expansion. The process by which the founding malignant clone generates subclones through the acquisition of additional driver mutations. In some patients, the order of genetic changes, i.e., the temporal order of acquisition of driver mutations, can be inferred by means of massive parallel sequencing though calculation of the mutant allele burden or variant allele frequency (VAF). 
• Intraclonal (intratumoral) heterogeneity. A founding malignant clone that has undergone subclonal evolution is no longer monoclonal in the strict sense, but is instead a mosaic of several clones/genomes with different sets of somatic mutations. 
Mutation: A change of the nucleotide sequence of the genome. 
• Germline mutation: A mutation that is inherited though a germ cell (oocyte or spermatozoon) at the time of conception, and is therefore present in all cells of a developed body. 
• Somatic mutation: A mutation that occurs in a non-germ cell of a body after conception (the ancient Greek somatikos means “of the body”). 
• Nonsynonymous mutation: A nucleotide mutation that alters the amino acid sequence of a protein. 
• Driver mutation: A mutation that causes a selective advantage in a cell with capacity for self-renewal, leading to formation of a clone of mutated cells. 
− Founding or initiating driver mutation: A driver mutation that gives rise to the initial clone of a malignancy. 
− Subclonal or cooperating driver mutation: A driver mutation that occurs in a cell of an already established clone and generates a subclone carrying both the founding and the newly acquired mutation. 
• Background or passenger mutation: A mutation that occurs in a tissue before neoplastic transformation and has no pathophysiological significance. In most tissues, including hematopoietic stem cells, the number of passenger mutations is a function of age. Whole genome sequencing studies have shown that in hematopoietic stem cells, their number may range from about 100 to 1000, depending on age. When an initiating driver mutation gives rise to a malignant clone (neoplastic transformation), all background or passenger mutations present at that time are captured and carried forward. Additional passengers mutations can be captured during subclonal evolution. 
Mutant allele burdenorVAF: The relative proportion of a mutant or variant allele (i.e., the allele carrying a somatic mutation) in a tissue or tumor sample. The mutant allele burden can be estimated using various approaches: i) by means of allele-specific quantitative PCR [e.g., the procedure employed for estimating the proportion of JAK2 (V617F)-mutant alleles in granulocytes from a patient with polycythemia vera]; or ii) more directly by assessing variant and wild-type reads using next-generation sequencing. A mutant allele burden or VAF of about 50% in regions of diploid DNA content in a homogeneous cell population (e.g., circulating granulocytes in myeloid neoplasms) suggest a fully clonal population of cells that are heterozygous for the mutation. In myeloid neoplasms, the mutant allele burden in a bone marrow sample is most commonly between 40 and 50% due to the presence of non-myeloid cells. 
Variant-allele clusters: Group of mutation with similar VAF, potentially belonging to the same clone or subclone. 
Whole exome sequencing: A procedure that allows to sequence all the coding regions (exomes) of a genome. 
Whole genome sequencing: A procedure that allows to sequence the coding and non coding regions of a genome. 
Clone: A group of cells that derive from a common parent cell and share its genome. 
• Malignant clone: A clone generated by the occurrence in the parent cell of a somatic mutation that alters the cell biology and function. 
• Founding or initiating clone: A malignant clone generated by a founding somatic mutation. 
• Subclone: A clone generated by the occurrence of an additional driver mutation in a cell of an already established clone. 
• Clonal architecture: Clonal composition of a neoplasm based on its clonal origin and subclonal evolution. 
• Clonal dominance: A condition in which most cells of a tissue belong to a clone. In myelodysplastic syndromes, about 85-90% of bone marrow cells are clonally derived. 
• Subclonal evolution or expansion. The process by which the founding malignant clone generates subclones through the acquisition of additional driver mutations. In some patients, the order of genetic changes, i.e., the temporal order of acquisition of driver mutations, can be inferred by means of massive parallel sequencing though calculation of the mutant allele burden or variant allele frequency (VAF). 
• Intraclonal (intratumoral) heterogeneity. A founding malignant clone that has undergone subclonal evolution is no longer monoclonal in the strict sense, but is instead a mosaic of several clones/genomes with different sets of somatic mutations. 
Mutation: A change of the nucleotide sequence of the genome. 
• Germline mutation: A mutation that is inherited though a germ cell (oocyte or spermatozoon) at the time of conception, and is therefore present in all cells of a developed body. 
• Somatic mutation: A mutation that occurs in a non-germ cell of a body after conception (the ancient Greek somatikos means “of the body”). 
• Nonsynonymous mutation: A nucleotide mutation that alters the amino acid sequence of a protein. 
• Driver mutation: A mutation that causes a selective advantage in a cell with capacity for self-renewal, leading to formation of a clone of mutated cells. 
− Founding or initiating driver mutation: A driver mutation that gives rise to the initial clone of a malignancy. 
− Subclonal or cooperating driver mutation: A driver mutation that occurs in a cell of an already established clone and generates a subclone carrying both the founding and the newly acquired mutation. 
• Background or passenger mutation: A mutation that occurs in a tissue before neoplastic transformation and has no pathophysiological significance. In most tissues, including hematopoietic stem cells, the number of passenger mutations is a function of age. Whole genome sequencing studies have shown that in hematopoietic stem cells, their number may range from about 100 to 1000, depending on age. When an initiating driver mutation gives rise to a malignant clone (neoplastic transformation), all background or passenger mutations present at that time are captured and carried forward. Additional passengers mutations can be captured during subclonal evolution. 
Mutant allele burdenorVAF: The relative proportion of a mutant or variant allele (i.e., the allele carrying a somatic mutation) in a tissue or tumor sample. The mutant allele burden can be estimated using various approaches: i) by means of allele-specific quantitative PCR [e.g., the procedure employed for estimating the proportion of JAK2 (V617F)-mutant alleles in granulocytes from a patient with polycythemia vera]; or ii) more directly by assessing variant and wild-type reads using next-generation sequencing. A mutant allele burden or VAF of about 50% in regions of diploid DNA content in a homogeneous cell population (e.g., circulating granulocytes in myeloid neoplasms) suggest a fully clonal population of cells that are heterozygous for the mutation. In myeloid neoplasms, the mutant allele burden in a bone marrow sample is most commonly between 40 and 50% due to the presence of non-myeloid cells. 
Variant-allele clusters: Group of mutation with similar VAF, potentially belonging to the same clone or subclone. 
Whole exome sequencing: A procedure that allows to sequence all the coding regions (exomes) of a genome. 
Whole genome sequencing: A procedure that allows to sequence the coding and non coding regions of a genome. 

For deeper insight into these concepts, the reader is referred to recent articles by Ley and colleagues3,4  and Vogelstein et al.6 

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