Serial Next-Generation Sequencing for Detection of Germline Predisposition in Acute Myeloid Leukemia
Year: 2024
Type: conference-abstract
Abstract: Somatic next-generation sequencing (NGS) panel are now routinely performed at diagnosis of acute myeloid leukemia (AML) to identify genetic variants for risk stratification and treatment decisions. The variant allele frequencies (VAF) suspected to be germline variants remain persistently high in complete remission (CR) state, allowing these variants to be identified as germline variants. The NGS panel used clinically for diagnosis includes representative genes associated with germline predisposition to myeloid neoplasms. Based on above information, we aimed to investigate the frequency of germline variants and their prognostic significance of AML in patients with matched samples at diagnosis and at CR state. We conducted a prospective multicenter study (KCT0004825) collecting serial samples from AML patients. The process of interpreting germline variants is performed according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines. We classified germline variants as causality if they were either ‘Pathogenic’ or ‘Likely Pathogenic’ by the ACMG guideline or if they were accompanied by a somatic mutation with ‘Variants of Uncertain Significance’. This study enrolled 603 patients diagnosed with treatable AML, excluding acute promyelocytic leukemia, between Feb. 2017 and Jun. 2021 from 17 institutions. Among these, paired CR samples were available for 343 patients who were eligible for NGS at diagnosis and after chemotherapies. We detected germline variants in 19 patients (5.5%). The most frequent germline mutations were in DDX41 (n=11, 58%) followed by DNAH5 (n=3, 16%), CEBPA and TP53 (both n=2, 11%), and MPL and GATA2 (both n=1, 5%). One patient harbored both TP53 and DNAH5 germline mutations. The mean VAF at diagnosis and CR samples were 48.9% [inter-quantile range (IQR): 47.8%-49.9%] and 48.0% (IQR: 47.6%-49.7%) respectively. Compared with non-germline mutated patients, patients with germline mutations were more hypoplastic (50% vs 80%, P < 0.001), and low bone marrow blast counts (34% vs. 65%, P=0.004). Germline mutations were not observed in the favorable cytogenetic risk group (0% vs. 23.1%, P= 0.03), and were rarely detected in 2022 European LeukemiaNet favorable risk group (5.3% vs. 47.5%, P <0.001), compared with non-germline mutated patients. Intensive chemotherapy was more frequently administered in the non-germline mutated group (P=0.022) but, there was no difference in the rate of allogeneic transplants between the two groups (P>0.05). Comparing survival rates, there was no difference between two groups that received intensive chemotherapy, nor was there a difference for those who underwent allogeneic transplantation (all, P>0.05). In conclusion, NGS analysis using matched CR samples proves to be an invaluable tool in detecting germline mutations. Since patients with germline mutations are rarely classified into the favorable risk category, most patients in this group should consider allogeneic transplantation. Although patients with germline mutations did not show significant prognostic differences in treatment outcomes due to the small number of patients, more studies involving a larger cohort are needed to determine the role of allogeneic transplantation.
Source: Blood
Authors: Jae-Sook Ahn, Joo Heon Park, Ik Chan Song, ChangSun Lee, Sang Kyun Sohn, Ho-Young Yhim, Yong Park, Inho Kim, Ho-Jin Shin, Seong Kyu Park, Sung-Hyun Kim, June-Won Cheong, Ho Sup Lee, Hyewon Lee, Sung Hwa Bae, Yunsuk Choi, Hong-Ghi Lee, Young Rok Do, Jae-Joon Han, Min Kyoung Kim, Silvia Park, Hee-Je Kim, Hyeoung-Joon Kim
Institutions: Chonnam National University Hwasun Hospital, Chonnam National University, Chungnam National University, Chungnam National University Hospital, Kyungpook National University Hospital, Jeonbuk National University Hospital, Jeonbuk National University, Korea University, Korea University Medical Center, Seoul National University Hospital, Pusan National University Hospital, Pusan National University, The Catholic University of Korea Seoul St. Mary's Hospital, Soonchunhyang University Hospital Bucheon, Catholic University of Korea, Dong-A University Hospital, Dong-A University, Yonsei University, Severance Hospital, Yonsei University Health System, Konkuk University, Kosin University Gospel Hospital, Konkuk University Medical Center, National Cancer Center, Daegu Catholic University, Daegu Catholic University Medical Center, Asan Medical Center, University of Ulsan, Keimyung University Dongsan Medical Center, Keimyung University, Kyung Hee University, Kyung Hee University Medical Center, Yeungnam University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405038793