P042: A next generation sequencing strategy for a comprehensive molecular diagnosis in chronic lymphocytic leukemia: Mexican experience

P042: A next generation sequencing strategy for a comprehensive molecular diagnosis in chronic lymphocytic leukemia: Mexican experience. Abreu, M., Martínez, L. V., Ceballos López, A. A., Prieto, A. V., García, Á. C., Court, M. D., Amatón Tabares, R. P., Carvajal Lohr, S. M., Galindo Ruvalcaba, C. H., Hernández, F. G., Rodríguez Muñoz, Y. F., Ancheyta, L. H., & Azotla Vilchis, C. O. Genetics in Medicine Open, 1(1):100061, March, 2023.

Paper doi abstract bibtex

Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, being the most common leukemia in adults in Western countries (30%), however is very rare in Asia and Latin America, including Mexico (7% in Mexican Mestizos). Although the different prevalence around populations, the clinical and molecular features of the disease are quite similar, with recurrent chromosomal abnormalities such as deletions in 13q14 (50%-60%), 11q (15%), 17p (10%) and trisomy 12 (15%). The most frequent gene variants occur in SF3B1 (10–15%) and NOTCH1 (~10%). Current prognostic and predictive biomarkers in patients with CLL are pathogenic variants in TP53, deletions in 17p and the mutational status of the immunoglobulin heavy-chain variable region (IGHV). As the genetic proﬁle of CLL is complex and multiple concurrent genetic variants are present, a comprehensive cost/effective NGS test was chosen to detect the informative genetic abnormalities in a cohort of 31 Mexican patients with CLL in different stages of treatment or follow up. Methods: Thirty-one CLL Mexican patients were clinical selected (monoclonal B lymphocytes ≥5 x 109/L with clonality of B cells conﬁrmed by ﬂow cytometry). NGS was performed using Sophia Genetics® CLL_V2 Custom panel that targets 15 genes: ATM, BIRC3, CXCR4, EGR2, FBXW7, KRAS, MYD88, NFKBIE, POT1 and TP53, as well as hotspots in BTK, NOTCH1, PLG2, SF3B1 and XPO1. This kit identiﬁes for \textgreater20% of cellular content copy number variants (CNVs) in KRAS, ATF1 and CDK4 (for trisomy 12); DLEU1, PROZ, KLF5, and CUL4A (for 13q deletion), ATM and TP53. For the bioinformatic analysis, the Sophia DDM® software was used and variants were classiﬁed as pathogenic/probably pathogenic according to ACMG guidelines (allelic frequency ≥5%). The analysis of the IG gene was performed from FASTQ ﬁles using the IgCaller Web and IMGT/V-QUEST software, where the IGHV is considered unmutated (IGHV-UM) if the identity with the germinal sequence is ≥98%. Results: A total of 31 patients were analyzed: 15 females and 16 males. 55% of the cases were from the northern part of the country (n=17), of which Sonora has the highest incidence with 11 cases (65%). At the time of the genetic analysis, only 6 patients (19%) were undergoing treatment, where 4 used BTK inhibitors and 2 chemotherapy. A biomarker with prognostic value was identiﬁed in 87% of the patients; 11/31 presented IGHV-UM, of which 73% of the cases were accompanied by at least one other genetic alteration (SNV or CNV) and 45% by two concomitant alterations. 13% of the patients had trisomy 12 and all were accompanied by an IGHV-UM. In 2/6 patients who were on treatment, an IGHV-UM and/or a pathogenic variant in TP53 was detected. Conclusion: The distribution and frequency of CLL in the north of Mexico is probably related to a greater European genetic contribution in this part of the country and this cohort shows a selective high incidence in this region, particularly Sonora. This all-in-one genomic strategy allows a comprehensive detection of the principal known and new prognostic CLL gene associations, CNV detection and IGHV mutational status, making possible to optimize time and economic resources in the management of CLL patients, which is extremely important in lowincome countries. Also, these broad genomic panel have made it possible to ﬁnd new associations of prognostic value in CLL, as appears to be trisomy 12 in Mexican patients who are been detected with IGHV-UM, having a worse prognosis.

@article{abreu_p042_2023,
	title = {P042: {A} next generation sequencing strategy for a comprehensive molecular diagnosis in chronic lymphocytic leukemia: {Mexican} experience},
	volume = {1},
	issn = {29497744},
	shorttitle = {P042},
	url = {https://linkinghub.elsevier.com/retrieve/pii/S2949774423000614},
	doi = {10.1016/j.gimo.2023.100061},
	abstract = {Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, being the most common leukemia in adults in Western countries (30\%), however is very rare in Asia and Latin America, including Mexico (7\% in Mexican Mestizos). Although the different prevalence around populations, the clinical and molecular features of the disease are quite similar, with recurrent chromosomal abnormalities such as deletions in 13q14 (50\%-60\%), 11q (15\%), 17p (10\%) and trisomy 12 (15\%). The most frequent gene variants occur in SF3B1 (10–15\%) and NOTCH1 ({\textasciitilde}10\%). Current prognostic and predictive biomarkers in patients with CLL are pathogenic variants in TP53, deletions in 17p and the mutational status of the immunoglobulin heavy-chain variable region (IGHV). As the genetic proﬁle of CLL is complex and multiple concurrent genetic variants are present, a comprehensive cost/effective NGS test was chosen to detect the informative genetic abnormalities in a cohort of 31 Mexican patients with CLL in different stages of treatment or follow up.
Methods: Thirty-one CLL Mexican patients were clinical selected (monoclonal B lymphocytes ≥5 x 109/L with clonality of B cells conﬁrmed by ﬂow cytometry). NGS was performed using Sophia Genetics® CLL\_V2 Custom panel that targets 15 genes: ATM, BIRC3, CXCR4, EGR2, FBXW7, KRAS, MYD88, NFKBIE, POT1 and TP53, as well as hotspots in BTK, NOTCH1, PLG2, SF3B1 and XPO1. This kit identiﬁes for {\textgreater}20\% of cellular content copy number variants (CNVs) in KRAS, ATF1 and CDK4 (for trisomy 12); DLEU1, PROZ, KLF5, and CUL4A (for 13q deletion), ATM and TP53. For the bioinformatic analysis, the Sophia DDM® software was used and variants were classiﬁed as pathogenic/probably pathogenic according to ACMG guidelines (allelic frequency ≥5\%). The analysis of the IG gene was performed from FASTQ ﬁles using the IgCaller Web and IMGT/V-QUEST software, where the IGHV is considered unmutated (IGHV-UM) if the identity with the germinal sequence is ≥98\%.
Results: A total of 31 patients were analyzed: 15 females and 16 males. 55\% of the cases were from the northern part of the country (n=17), of which Sonora has the highest incidence with 11 cases (65\%). At the time of the genetic analysis, only 6 patients (19\%) were undergoing treatment, where 4 used BTK inhibitors and 2 chemotherapy. A biomarker with prognostic value was identiﬁed in 87\% of the patients; 11/31 presented IGHV-UM, of which 73\% of the cases were accompanied by at least one other genetic alteration (SNV or CNV) and 45\% by two concomitant alterations. 13\% of the patients had trisomy 12 and all were accompanied by an IGHV-UM. In 2/6 patients who were on treatment, an IGHV-UM and/or a pathogenic variant in TP53 was detected.
Conclusion: The distribution and frequency of CLL in the north of Mexico is probably related to a greater European genetic contribution in this part of the country and this cohort shows a selective high incidence in this region, particularly Sonora. This all-in-one genomic strategy allows a comprehensive detection of the principal known and new prognostic CLL gene associations, CNV detection and IGHV mutational status, making possible to optimize time and economic resources in the management of CLL patients, which is extremely important in lowincome countries. Also, these broad genomic panel have made it possible to ﬁnd new associations of prognostic value in CLL, as appears to be trisomy 12 in Mexican patients who are been detected with IGHV-UM, having a worse prognosis.},
	language = {en},
	number = {1},
	urldate = {2023-05-10},
	journal = {Genetics in Medicine Open},
	author = {Abreu, Melania and Martínez, Luis Villela and Ceballos López, Adrián Alejandro and Prieto, Alberto Villalobos and García, Álvaro Cabrera and Court, Marcela Deffis and Amatón Tabares, René Porfirio and Carvajal Lohr, Siria María and Galindo Ruvalcaba, Cesar Humberto and Hernández, Federico Godínez and Rodríguez Muñoz, Yolanda Fabiola and Ancheyta, Lizbeth Hernández and Azotla Vilchis, Coztli Ocelotl},
	month = mar,
	year = {2023},
	keywords = {CLL, CLL v2, Chronic lymphocytic leukaemia, Custom Panel, DDM},
	pages = {100061},
}

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O."],"bibdata":{"bibtype":"article","type":"article","title":"P042: A next generation sequencing strategy for a comprehensive molecular diagnosis in chronic lymphocytic leukemia: Mexican experience","volume":"1","issn":"29497744","shorttitle":"P042","url":"https://linkinghub.elsevier.com/retrieve/pii/S2949774423000614","doi":"10.1016/j.gimo.2023.100061","abstract":"Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, being the most common leukemia in adults in Western countries (30%), however is very rare in Asia and Latin America, including Mexico (7% in Mexican Mestizos). Although the different prevalence around populations, the clinical and molecular features of the disease are quite similar, with recurrent chromosomal abnormalities such as deletions in 13q14 (50%-60%), 11q (15%), 17p (10%) and trisomy 12 (15%). The most frequent gene variants occur in SF3B1 (10–15%) and NOTCH1 (~10%). Current prognostic and predictive biomarkers in patients with CLL are pathogenic variants in TP53, deletions in 17p and the mutational status of the immunoglobulin heavy-chain variable region (IGHV). As the genetic proﬁle of CLL is complex and multiple concurrent genetic variants are present, a comprehensive cost/effective NGS test was chosen to detect the informative genetic abnormalities in a cohort of 31 Mexican patients with CLL in different stages of treatment or follow up. Methods: Thirty-one CLL Mexican patients were clinical selected (monoclonal B lymphocytes ≥5 x 109/L with clonality of B cells conﬁrmed by ﬂow cytometry). NGS was performed using Sophia Genetics® CLL_V2 Custom panel that targets 15 genes: ATM, BIRC3, CXCR4, EGR2, FBXW7, KRAS, MYD88, NFKBIE, POT1 and TP53, as well as hotspots in BTK, NOTCH1, PLG2, SF3B1 and XPO1. This kit identiﬁes for \\textgreater20% of cellular content copy number variants (CNVs) in KRAS, ATF1 and CDK4 (for trisomy 12); DLEU1, PROZ, KLF5, and CUL4A (for 13q deletion), ATM and TP53. For the bioinformatic analysis, the Sophia DDM® software was used and variants were classiﬁed as pathogenic/probably pathogenic according to ACMG guidelines (allelic frequency ≥5%). The analysis of the IG gene was performed from FASTQ ﬁles using the IgCaller Web and IMGT/V-QUEST software, where the IGHV is considered unmutated (IGHV-UM) if the identity with the germinal sequence is ≥98%. Results: A total of 31 patients were analyzed: 15 females and 16 males. 55% of the cases were from the northern part of the country (n=17), of which Sonora has the highest incidence with 11 cases (65%). At the time of the genetic analysis, only 6 patients (19%) were undergoing treatment, where 4 used BTK inhibitors and 2 chemotherapy. A biomarker with prognostic value was identiﬁed in 87% of the patients; 11/31 presented IGHV-UM, of which 73% of the cases were accompanied by at least one other genetic alteration (SNV or CNV) and 45% by two concomitant alterations. 13% of the patients had trisomy 12 and all were accompanied by an IGHV-UM. In 2/6 patients who were on treatment, an IGHV-UM and/or a pathogenic variant in TP53 was detected. Conclusion: The distribution and frequency of CLL in the north of Mexico is probably related to a greater European genetic contribution in this part of the country and this cohort shows a selective high incidence in this region, particularly Sonora. This all-in-one genomic strategy allows a comprehensive detection of the principal known and new prognostic CLL gene associations, CNV detection and IGHV mutational status, making possible to optimize time and economic resources in the management of CLL patients, which is extremely important in lowincome countries. Also, these broad genomic panel have made it possible to ﬁnd new associations of prognostic value in CLL, as appears to be trisomy 12 in Mexican patients who are been detected with IGHV-UM, having a worse prognosis.","language":"en","number":"1","urldate":"2023-05-10","journal":"Genetics in Medicine Open","author":[{"propositions":[],"lastnames":["Abreu"],"firstnames":["Melania"],"suffixes":[]},{"propositions":[],"lastnames":["Martínez"],"firstnames":["Luis","Villela"],"suffixes":[]},{"propositions":[],"lastnames":["Ceballos","López"],"firstnames":["Adrián","Alejandro"],"suffixes":[]},{"propositions":[],"lastnames":["Prieto"],"firstnames":["Alberto","Villalobos"],"suffixes":[]},{"propositions":[],"lastnames":["García"],"firstnames":["Álvaro","Cabrera"],"suffixes":[]},{"propositions":[],"lastnames":["Court"],"firstnames":["Marcela","Deffis"],"suffixes":[]},{"propositions":[],"lastnames":["Amatón","Tabares"],"firstnames":["René","Porfirio"],"suffixes":[]},{"propositions":[],"lastnames":["Carvajal","Lohr"],"firstnames":["Siria","María"],"suffixes":[]},{"propositions":[],"lastnames":["Galindo","Ruvalcaba"],"firstnames":["Cesar","Humberto"],"suffixes":[]},{"propositions":[],"lastnames":["Hernández"],"firstnames":["Federico","Godínez"],"suffixes":[]},{"propositions":[],"lastnames":["Rodríguez","Muñoz"],"firstnames":["Yolanda","Fabiola"],"suffixes":[]},{"propositions":[],"lastnames":["Ancheyta"],"firstnames":["Lizbeth","Hernández"],"suffixes":[]},{"propositions":[],"lastnames":["Azotla","Vilchis"],"firstnames":["Coztli","Ocelotl"],"suffixes":[]}],"month":"March","year":"2023","keywords":"CLL, CLL v2, Chronic lymphocytic leukaemia, Custom Panel, DDM","pages":"100061","bibtex":"@article{abreu_p042_2023,\n\ttitle = {P042: {A} next generation sequencing strategy for a comprehensive molecular diagnosis in chronic lymphocytic leukemia: {Mexican} experience},\n\tvolume = {1},\n\tissn = {29497744},\n\tshorttitle = {P042},\n\turl = {https://linkinghub.elsevier.com/retrieve/pii/S2949774423000614},\n\tdoi = {10.1016/j.gimo.2023.100061},\n\tabstract = {Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, being the most common leukemia in adults in Western countries (30\\%), however is very rare in Asia and Latin America, including Mexico (7\\% in Mexican Mestizos). Although the different prevalence around populations, the clinical and molecular features of the disease are quite similar, with recurrent chromosomal abnormalities such as deletions in 13q14 (50\\%-60\\%), 11q (15\\%), 17p (10\\%) and trisomy 12 (15\\%). The most frequent gene variants occur in SF3B1 (10–15\\%) and NOTCH1 ({\\textasciitilde}10\\%). Current prognostic and predictive biomarkers in patients with CLL are pathogenic variants in TP53, deletions in 17p and the mutational status of the immunoglobulin heavy-chain variable region (IGHV). As the genetic proﬁle of CLL is complex and multiple concurrent genetic variants are present, a comprehensive cost/effective NGS test was chosen to detect the informative genetic abnormalities in a cohort of 31 Mexican patients with CLL in different stages of treatment or follow up.\nMethods: Thirty-one CLL Mexican patients were clinical selected (monoclonal B lymphocytes ≥5 x 109/L with clonality of B cells conﬁrmed by ﬂow cytometry). NGS was performed using Sophia Genetics® CLL\\_V2 Custom panel that targets 15 genes: ATM, BIRC3, CXCR4, EGR2, FBXW7, KRAS, MYD88, NFKBIE, POT1 and TP53, as well as hotspots in BTK, NOTCH1, PLG2, SF3B1 and XPO1. This kit identiﬁes for {\\textgreater}20\\% of cellular content copy number variants (CNVs) in KRAS, ATF1 and CDK4 (for trisomy 12); DLEU1, PROZ, KLF5, and CUL4A (for 13q deletion), ATM and TP53. For the bioinformatic analysis, the Sophia DDM® software was used and variants were classiﬁed as pathogenic/probably pathogenic according to ACMG guidelines (allelic frequency ≥5\\%). The analysis of the IG gene was performed from FASTQ ﬁles using the IgCaller Web and IMGT/V-QUEST software, where the IGHV is considered unmutated (IGHV-UM) if the identity with the germinal sequence is ≥98\\%.\nResults: A total of 31 patients were analyzed: 15 females and 16 males. 55\\% of the cases were from the northern part of the country (n=17), of which Sonora has the highest incidence with 11 cases (65\\%). At the time of the genetic analysis, only 6 patients (19\\%) were undergoing treatment, where 4 used BTK inhibitors and 2 chemotherapy. A biomarker with prognostic value was identiﬁed in 87\\% of the patients; 11/31 presented IGHV-UM, of which 73\\% of the cases were accompanied by at least one other genetic alteration (SNV or CNV) and 45\\% by two concomitant alterations. 13\\% of the patients had trisomy 12 and all were accompanied by an IGHV-UM. In 2/6 patients who were on treatment, an IGHV-UM and/or a pathogenic variant in TP53 was detected.\nConclusion: The distribution and frequency of CLL in the north of Mexico is probably related to a greater European genetic contribution in this part of the country and this cohort shows a selective high incidence in this region, particularly Sonora. This all-in-one genomic strategy allows a comprehensive detection of the principal known and new prognostic CLL gene associations, CNV detection and IGHV mutational status, making possible to optimize time and economic resources in the management of CLL patients, which is extremely important in lowincome countries. Also, these broad genomic panel have made it possible to ﬁnd new associations of prognostic value in CLL, as appears to be trisomy 12 in Mexican patients who are been detected with IGHV-UM, having a worse prognosis.},\n\tlanguage = {en},\n\tnumber = {1},\n\turldate = {2023-05-10},\n\tjournal = {Genetics in Medicine Open},\n\tauthor = {Abreu, Melania and Martínez, Luis Villela and Ceballos López, Adrián Alejandro and Prieto, Alberto Villalobos and García, Álvaro Cabrera and Court, Marcela Deffis and Amatón Tabares, René Porfirio and Carvajal Lohr, Siria María and Galindo Ruvalcaba, Cesar Humberto and Hernández, Federico Godínez and Rodríguez Muñoz, Yolanda Fabiola and Ancheyta, Lizbeth Hernández and Azotla Vilchis, Coztli Ocelotl},\n\tmonth = mar,\n\tyear = {2023},\n\tkeywords = {CLL, CLL v2, Chronic lymphocytic leukaemia, Custom Panel, DDM},\n\tpages = {100061},\n}\n\n\n\n\n\n\n\n\n\n\n\n","author_short":["Abreu, M.","Martínez, L. V.","Ceballos López, A. A.","Prieto, A. V.","García, Á. C.","Court, M. D.","Amatón Tabares, R. P.","Carvajal Lohr, S. M.","Galindo Ruvalcaba, C. H.","Hernández, F. G.","Rodríguez Muñoz, Y. F.","Ancheyta, L. H.","Azotla Vilchis, C. O."],"key":"abreu_p042_2023","id":"abreu_p042_2023","bibbaseid":"abreu-martnez-ceballoslpez-prieto-garca-court-amatntabares-carvajallohr-etal-p042anextgenerationsequencingstrategyforacomprehensivemoleculardiagnosisinchroniclymphocyticleukemiamexicanexperience-2023","role":"author","urls":{"Paper":"https://linkinghub.elsevier.com/retrieve/pii/S2949774423000614"},"keyword":["CLL","CLL v2","Chronic lymphocytic leukaemia","Custom Panel","DDM"],"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://bibbase.org/zotero/SOPHiAGENETICS","dataSources":["Pcpsxmwz8uxXtL843"],"keywords":["cll","cll v2","chronic lymphocytic leukaemia","custom panel","ddm"],"search_terms":["p042","next","generation","sequencing","strategy","comprehensive","molecular","diagnosis","chronic","lymphocytic","leukemia","mexican","experience","abreu","martínez","ceballos lópez","prieto","garcía","court","amatón tabares","carvajal lohr","galindo ruvalcaba","hernández","rodríguez muñoz","ancheyta","azotla vilchis"],"title":"P042: A next generation sequencing strategy for a comprehensive molecular diagnosis in chronic lymphocytic leukemia: Mexican experience","year":2023}