Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma

• Published in: Cancer Science Vol. 110; no. 1; pp. 401 - 407
• Main Authors: 服部 圭一郎, 高野 晋吾, 坂田（柳元） 麻実子, 日下部 学, 野口 雅之, 横山 泰久, 加藤 貴康, 栗田 尚樹, 錦井 秀和, 小原 直, 石川 栄一, 松村 明, 村谷 匡史, 長谷川 雄一, 千葉 滋, Hattori Keiichiro, Nanmoku Toru, Suehara Yasuhito, Noguchi Masayuki, Yokoyama Yasuhisa
• Format: Journal Article
• Language: English
• Published: England wiley 01.01.2019; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: Aged; Bone marrow; Bone tumors; Cell differentiation; Central nervous system; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - metabolism; Central Nervous System Neoplasms - pathology; common precursor cell; Female; Gene Rearrangement; Genomes; Heavy chains; High-Throughput Nucleotide Sequencing; Humans; IgH rearrangement; Immunoglobulin Heavy Chains - genetics; Immunoglobulins; L265P MYD88; Leukocytes (mononuclear); Lymphatic system; Lymphoma; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Male; Middle Aged; Mutation; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Neoplasm Recurrence, Local; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nervous system; NMR; Nuclear magnetic resonance; Original; Patients; Polymerase chain reaction; primary central nervous system lymphoma; Tumors; United States > US; IgH rearrangement; common precursor cell; L265P MYD88; bone marrow; primary central nervous system lymphoma
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13848

Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra- CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precur -sor cells (CPC) for primary intra- and relapsed extra- CNS tumors, and further assess -ing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra- and relapsed extra- CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra- and extra- CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra- CNS tumors and in four out of five extra- CNS tumors. Remarkably, IgH clones in the intra- and the extra- CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonalIgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor- free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutationswere detected by a droplet digital PCR method in nine out of 23 bone marrow mono -nuclear cells. These results suggest that intra- and extra- tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rear-rangement. The initiatingMYD88 mutations may occur during B- cell differentiation in BM.