Genotype–phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype–phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype–phenotype correlations encouraging further analyses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-022-01332-1

Long-term disease-free survival in patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND AND OBJECTIVES: Patients with angioimmunoblastic T-cell lymphoma (AIL) have a poor prognosis with conventional treatment. DESIGN AND METHODS: We initiated an EBMT-based survey studying the impact of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation in patients with AIL. Data on 29 patients, who were transplanted between 1992 and 1998 in 16 transplant centers, were collected on standardized documentation forms. RESULTS: The median age at transplantation was 53 years. HDCT was given as part of 1st-line therapy (N=14; 48%) or 2nd/3rd-line therapy (N=15; 52%). Regimens for the mobilization of peripheral blood stem cells (PBSC) included VIPE (N=7; 26%), DexaBEAM (N=6; 22%), CHOP-like regimens (N=6; 22%), other regimens (N=5; 19%) or alternatively growth factor alone (N=3; 11%). The median yield of PBSC was 3.8x106 CD34+cells/kg. Two patients received autologous bone marrow. The HDCT consisted of BEAM-type regimens in 16 patients, ICE-type regimens in 7, and other regimens in 6 patients. There was one treatment-related death. The rate of complete remissions increased from 45% before HDCT to 76% after HDCT. As of January 2003, after a median observation time of living patients of 5 years (range 2.5 to 10 years), 14 patients have died (13 from progressive disease), and 15 patients are alive. The probability of 5-year overall and event-free survival was 44% (95% CI, 22% to 66%) and 37% (95% CI, 17% to 57%), respectively. Long-term disease-free survival was observed in patients transplanted during 1st-line treatment as well as in the context of 2nd/3rd-line therapy. INTERPRETATION AND CONCLUSIONS: There is evidence that AIL is susceptible to high-dose chemotherapy. HDCT and autologous stem cell transplantation should be considered in selected patients with AIL

Prognostic impact of nutritional and inflammation-based risk scores in follicular lymphoma in the era of anti-CD20 targeted treatment strategies

Background!#!The composition of the tumor microenvironment (TME) is conditioned by immunity and the inflammatory response. Nutritional and inflammation-based risk scores have emerged as relevant predictors of survival outcome across a variety of hematological malignancies.!##!Methods!#!In this retrospective multicenter trial, we ascertained the prognostic impact of established nutritional and inflammation-based risk scores [Glasgow Prognostic Score (GPS), C-reactive-protein/albumin ratio (CAR), neutrophil-lymphocyte ratio (NLR), prognostic nutritional index (PNI), and prognostic index (PI)] in 209 eligible patients with histologically confirmed CD20!##!Results!#!In the study cohort, the median age was 63 (range 22-90 years). The median follow-up period covered 99 months. The GPS and the CAR were identified to predict survival in FL patients. The GPS was the only independent predictor of OS (p &amp;lt; 0.0001; HR 2.773; 95% CI 1.630-4.719) and PFS (p = 0.001; HR 1.995; 95% CI 1.352-2.944) upon multivariate analysis. Additionally, there was frequent occurrence of progression of disease within 24 months (POD24) in FL patients with a calculated GPS of 2.!##!Conclusion!#!The current results indicate that the GPS predicts especially OS in FL patients. Moreover, GPS was found to display disease-specific effects in regard to FL progression. These findings and potential combinations with additional established prognosticators should be further validated within prospective clinical trials

NRG1 fusions in KRAS wild-type pancreatic cancer

Abstract We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with KRAS wild-type (KRASWT) tumors (4 of 17). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor–mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASWT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC. Significance: Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as NRG1 fusions as disease-driving events in KRASwt tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. Cancer Discov; 8(9); 1087–95. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1047</jats:p