Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma
Authors: Jason Yongsheng Chan, Alvin Yu Jin Ng, Chee Leong Cheng, Maarja-Liisa Nairismägi, Byrappa Venkatesh, Daryl Ming Zhe Cheah, Shao-Tzu Li, Sock Hoai Chan, Joanne Ngeow, Yurike Laurensia, Jing Quan Lim, Jane Wan Lu Pang, Sanjanaa Nagarajan, Tammy Song, Burton Chia, Jing Tan, Dachuan Huang, Yeow Tee Goh, Eileen Poon, Nagavalli Somasundaram, Miriam Tao, Richard Hong Hui Quek, Mohamad Farid, Chiea Chuen Khor, Jin-Xin Bei, Soo Yong Tan, Soon Thye Lim, Choon Kiat Ong, Tiffany Tang
Journal: Blood Cancer Journal (2018)

Natural-killer/T-cell lymphoma (NKTL) is a rare subset of non-Hodgkin lymphoma that demonstrates a unique geographic distribution, with higher prevalence in Asia compared to the West1. While cure remains achievable in early-stage disease, the prognosis for advanced-stage NKTL is dismal2. Recently, some progress has been made in uncovering the molecular pathogenesis of NKTL. In a genome-wide association study, strong correlations between HLA-DPB1 single-nucleotide polymorphisms and NKTL susceptibility were discovered, implicating altered antigen processing and presentation to CD4-positive T-lymphocytes in this Epstein-Barr virus (EBV)-associated malignancy3. Next generation sequencing also revealed recurrent somatic mutations such as TP53, JAK3, STAT3 and DDX3X in NKTL4,5. In this paper, we report a pair of male siblings from a non-consanguineous Chinese family who were diagnosed with NKTL, and provide initial evidence for novel recessive germline mutations in FAM160A1 identified through next-generation sequencing.

The index patient was 35 years old, when he presented with nasal blockage in March 2013. 18-FDG-PET/CT imaging revealed an 18-FDG-avid nasal mass infiltrating into the palate, as well as enlarged cervical lymph nodes. Biopsy of the mass showed abnormal lymphoid cells positive for CD56 by immunohistochemistry (IHC) as well as EBV-encoded RNA (EBER) by in-situ hybridization. He was diagnosed with stage IIA extranodal NKTL, nasal type, and treated with 4 cycles of bortezomib-GIFOX (gemcitabine, ifosfamide and oxaliplatin) as part of a clinical trial followed by radiotherapy to the nasal region. He had primary-refractory disease and was further treated with 4 cycles of SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) followed by high-dose chemotherapy and autologous stem cell transplantation. He progressed and received ruxolitinib off-label, followed by RAD001 (mTOR inhibitor) and LBH589B (histone deacetylase inhibitor) as part of another clinical trial. He then had radiotherapy to an ulcerating penile lesion before he died of progressive disease 27 months after diagnosis (Supplementary Table 1).

His younger brother was 18 years old, when diagnosed with NKTL affecting the nasal floor in 1998 following a bout of epistaxis. He received 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with high-dose methotrexate and went into complete remission. Three years later he was diagnosed with chronic myeloid leukemia, for which he received hydroxyurea. In 2004, he had a relapse of NKTL and received ESHAP (etoposide, prednisolone, cytarabine and cisplatin), total body irradiation and allogeneic bone marrow transplant. He died of transplant-related complications 6 years from diagnosis. These siblings have an older brother unaffected by any hematological malignancy. Their father died of a non-malignant condition in his fifties and their mother remains well at the age of 68 years. Among their first-degree relatives, none were known to be inflicted with hematologic malignancies (Fig. ​(Fig.11).






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Fig. 1

Clinical characterization of brothers with familial NKTL.
a 18-FDG-PET/CT image depicting a large nasal mass infiltrating into the palate, of which biopsy showed abnormal lymphoid cells positive for Epstein-Barr virus encoded RNA (EBER) by in situ hybridization. b, c Inheritance modelling identified homozygous germline mutations of FAM160A1 c.2827 C > T in both affected brothers, heterozygous carriage in their mother and paternal aunt, and homozygous wildtype in their healthy older brother. d, e The non-synonymous substitution at FAM160A1 c.2827 C > T results in an amino-acid alteration from arginine to cysteine (p.R943C). Patterns and frequencies of known mutations in other cancer types are shown