Tumor protein p53 (TP53) is the most frequently mutated gene in cancer 1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease 3,4 , rapid transformation to acute myeloid leukemia (AML) 5 , resistance to conventional therapies 6-8 and dismal outcomes 9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono-and biallelic mutations 10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R) 11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response. In collaboration with the International Working Group for Prognosis in MDS (Supplementary Table 1), we assembled a cohort of 3,324 peridiagnostic and treatment-naive patients with MDS or closely related myeloid neoplasms (Extended Data Fig. 1 and Supplementary Fig. 1). Genetic profiling included conventional G-banding analyses (CBA) and tumor-only, capture-based, next-generation sequencing (NGS) of a panel of genes recurrently mutated in MDS, as well as genome-wide copy number probes. Allele-specific copy number profiles were generated from NGS data using the CNACS algorithm 7 (see Methods and Code availability). An additional 1,120 samples derived from the Japanese MDS consortium (Extended Data Fig. 2) were used as a validation cohort. To study the effect of TP53 allelic state on genome stability, clinical presentation, outcome and response to therapy, we performed a detailed characterization of alterations at the TP53 locus. First, we assessed genome-wide allelic imbalances in the cohort of 3,324 patients, to include arm-level or focal (~3 Mb) ploidy alterations and regions of copy-neutral loss of heterozygosity (cnLOH) (Extended Data Fig. 3, Supplementary Figs. 2-4 and Methods).

No abstract

TP53 mutations are associated with poor clinical outcomes and treatment resistance in myelodysplastic syndromes. However, the biological and clinical relevance of the underlying mono-or bi-allelic state of the mutations is unclear. We analyzed 3,324 MDS patients for TP53 mutations and allelic imbalances of the TP53 locus and found that 1 in 3 TP53 -mutated patients had mono-allelic targeting of the gene whereas 2 in 3 had multiple hits consistent with bi-allelic targeting. The established associations for TP53 with complex karyotype, high-risk presentation, poor survival and rapid leukemic transformation were specific to patients with multi-hit state only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System, while mono-allelic patients did not differ from TP53 wild-type patients. The separation by allelic state was retained in therapy-related MDS. Findings were validated in a cohort of 1,120 patients. Ascertainment of TP53 allelic state is critical for diagnosis, risk estimation and prognostication precision in MDS, and future correlative studies of treatment response should consider TP53 allelic state.

Anemia is the defining feature in most patients with myelodysplastic syndromes (MDS), yet defects in erythropoiesis have not been well characterized. We examined freshly obtained bone marrow (BM) samples for stage-specific abnormalities during terminal erythroid differentiation (TED) from 221 samples (MDS, n = 205 from 113 unique patients; normal, n = 16) by measuring the surface expression of glycophorin A, band 3, and integrin α-4. Clinical and biologic associations were sought with presence or absence of TED and the specific stage of erythroid arrest. In 27% of MDS samples (56/205), there was no quantifiable TED documented by surface expression of integrin α-4 and band 3 by terminally differentiating erythroblasts. Absence of quantifiable TED was associated with a significantly worse overall survival (56 vs 103 months, = .0001) and mutations (7/23, < .05). In a multivariable Cox proportional hazards regression analysis, absence of TED remained independently significant across International Prognostic Scoring System-Revised (IPSS-R) categories, myeloid/erythroid ratio, and mutations in several genes. In 149/205 MDS samples, the proportion of cells undergoing TED did not follow the expected 1:2:4:8:16 doubling pattern in successive stages. Absence of TED emerged as a powerful independent prognostic marker of poor overall survival across all IPSS-R categories in MDS, and SRSF2 mutations were more frequently associated with absence of TED.

Primary malignant breast lymphoma (PBL) is a rare disease with an incidence of 0.04-0.5% of all malignant breast neoplasms. The majority of cases are B-cell lymphomas and the most common histologic type is diffuse large B-cell lymphoma (DLCL). In this study, we report our experience with three cases of PBL. The treatment was the same currently indicated for early stage aggressive NHL, i.e. anthracycline based chemotherapy followed by the involved field radiation therapy. Unfortunately, two patients underwent mastectomy to carry out correct diagnosis. The three patients are alive without any evidence of relapse after 24, 67 and 135 months of follow-up. Considering that aggressive NHL is very sensitive to chemotherapy, mastectomy should be avoided to preserve the quality of life of these patients, once surgery does not change the good prognosis of PBL.