Table 2.

Summary of major studies associating L-CH with lymphoid malignancy.

Publication	Technique	Cohort	Major Findings	Ref.
Jacobs et al. (2012)	Detection of mCAs in blood from one or more Infinium Human SNP Arrays	57,853 individuals from 13 genome-wide association studies	22% of individuals with lymphocytic leukemia had detectable clonal mosaicism at least 1 year prior, compared to 0.74% of cancer-free individuals. CLL was the predominant variety of lymphocytic leukemia, with frequent mosaic deletion of 13q14.	[13]
Laurie et al. (2012)	Detection of mCAs in blood from one of five Illumina array types	8,562 individuals from 15 studies belonging to the Gene Environment Association Studies consortium	Of 15 individuals with clonal mosaicism and subsequent hematologic cancer, 6 would develop CLL and 1 would develop MM. Of the 6 CLL cases, 5 bore the 13q deletion.	[14]
Schick et al. (2013)	Detection of mCAs in blood from one of four Illumina array types	12,176 individuals from the Group Health electronic Medical Records and Genomics study and the Women’s Health Initiative	mCAs appear to rarely precede the development of MM (1/46) or HL (0/6) by greater than 1 year.	[26]
Barrio et al. (2017)	Detection of somatic mutations by targeted deep sequencing of 24 genes implicated in CLL	48 individuals with high-count MBL	Mutations in high-count MBL significantly overlap with CLL. MBL carrying a mutation in one of 24 CLL genes posed a greater risk to CLL progression than MBL with no somatic mutation detected. Subclonal expansion of mutation-carrying MBL clones is predictive of progression to CLL.	[37]
Agathangelidis et al. (2018)	Detection of somatic mutations using Illumina Nextera WGS kit (VAF > 10%)	29 individuals with either MBL or CLL diagnosis	Somatic mutations identified in MBL significantly overlap with CLL driver genes.	[36]
Loh et al. (2018)	Detection of mCAs in blood from Affymetrix UK BiLEVE and UK Biobank AXIOM microarrays	152,248 individuals from the UK Biobank between 40 and 70 years of age at time of blood collection.	Incidence of CLL is positively correlated with the presence of Trisomy 3 and 12 as well as 13q LOH. Size of the clonal fraction is inversely correlated with the time to CLL diagnosis.	[11]
Terao et al. (2020)	Detection of mCAs in blood from one or more Infinium Human SNP Arrays	179,417 individuals from the Biobank Japan cohort	Common mutational precursors of CLL (trisomy 12, 13q deletion, and 13q LOH) were less frequent in Japanese individuals compared to the UK Biobank cohort. Selective pressure for specific mCAs varies with genetic background, consistent with the lower rates of CLL and higher rates of T-cell leukemia in the Japanese.	[28]
Niroula et al. (2021)	Detection of SNVs/indels in WES data at 56 M-CH related genes and 235 genes recurrently mutated in lymphoid malignancy (VAF > 2%). mCAs were previously detected in a prior study. CH and mCAs were excluded if they were detected less than 6 months before a hematologic malignancy diagnosis.	420,969 individuals with SNP microarray data and 55,383 individuals with WES from the UK Biobank and Mass General Brigham Biobank	CHIP occurs at both M-CHIP/M-mCA and L-CHIP/L-mCA loci and increases with age. M-CH and L-CH loci clearly segregate on the incidence myeloid and lymphoid malignancy. M-CHIP is dominated by DNMT3A, TET2, and ASXL1 somatic mutants, while L-CHIP is spread more evenly across a large number of genes. CLL was the dominant lymphoid malignancy occurring subsequent to L-CH.	[17]
Saiki et al. (2021)	Detection of SNVs/indels by targeted sequencing of 23 CH-associated genes (predominantly M-CH, VAF > 0.5%) and detection of CNAs by one of three Illumina array types	11,234 individuals without hematologic malignancy from the Biobank Japan cohort	Detection of CH strongly correlated with subsequent death attributable to myeloid malignancy (160/215) but only weakly with lymphoid malignancy (191/420) compared to non-hematologic malignancy death controls (4,209/10,562). These observations held true for all myeloid malignancy subtypes and lymphoid malignancy subtypes except CLL (7/7) and ALL (7/12).	[27]
Schroers-Martin et al. (2021)	Detection of somatic mutations by targeted deep sequencing of commonly mutated lymphoma driver genes.	29 individuals with subsequent follicular lymphoma diagnosis and 34 healthy controls from the American Cancer Society Cancer Prevention Study-II LifeLink cohort	Somatic mutations in t(14;18) positive follicular lymphoma can be detected years prior to diagnosis in low-frequency t(14;18) positive precursor cells.	[46]
Coffey et al. (2021)	Detection of somatic mutations in immunophenotyped blood cells by targeted single-cell DNA sequencing of 22 genes recurrently mutated in MM and CHIP	12 individuals with diagnosed MM	Somatic mutations detected in peripheral blood plasma cells were also identified in other hematopoietic lineages, indicating a bone marrow mutational origin for the MM precursor lesion.	[59]
Kar et al. (2022)	Detection of SNVs/indels by WES of peripheral blood DNA with the IDT xGen Exome Research Panel v1.0. SNVs/indels were characterized for 43 CH-related genes (predominantly M-CH)	200,453 individuals from the UK Biobank	Among the 43 CH-related genes, the incidence of lymphoid leukemia only increases significantly when the VAF exceeded 10% without an incident myeloid malignancy	[16]