TP53 Mutations in Myeloid Neoplasm Patients with and without Significant Personal and Family History of Cancer
Authors: Colombari Figueroa Sophia , Patel Bhumika J. , Barot Shimoli Vipul , Kuzmanovic Teodora , Nazha Aziz , Hsi Eric D. , Cook James R. , Mukherjee Sudipto , Gerds Aaron T. , Sekeres Mikkael A. , Kalaycio Matt , Advani Anjali S. , Maciejewski Jaroslaw P. , Carraway Hetty E. 
Published: October 2019

Abstract

Background: Next generation sequencing (NGS) of bone marrow or peripheral blood is increasingly being used in the upfront evaluation of patients with a new diagnosis of myeloid neoplasm (MN). This testing identifies salient mutations that are relevant in the biology of MN. Information obtained from NGS can inform patients and their family members about potential predisposition to current and future cancer diagnosis. Informing patients of the utility of NGS testing with regard to detection of GL risk as well as its current use in detection of somatic mutations is important. Additional relevant family history data can be combined in the clinical context of patient's personal oncologic history with the presence of a variant allele frequency (VAF) >30%-50% to enhance the prediction of GL predisposition. However, there is not a current consensus/guideline for further evaluation for possible GL predisposition for MN patients in the era of NGS results.
Methods: At our institution, we identified 401 patients with the diagnosis of MN who were sequenced by NGS from 2012-2017. We performed a retrospective review of this panel of patients to identify specific characteristics that may warrant further GL testing. Among these, we focused our study on MN patients that harbored a TP53 mutation (N=66), although future work will include patients with other mutations including but not limited to genes such as RUNX1, GATA2, and ETV6 which are also known to be associated with GL predisposition to MN. We collected demographic information, specific diagnosis, personal history of cancer and corresponding treatment, family history of cancer in first and second degree relatives as well as cytogenetic abnormalities. The location, variant allele frequency (VAF), mutation type, and significance for each TP53 mutation was annotated. Additional mutations in any of the 36 other disease-relevant genes such as ASXL1, BCOR, JAK2 were also fully annotated.
Results: In our cohort of 66 patients, 27 were females and 39 were males. AML/ALL was the most common diagnosis (32/66; 48.5%) followed by 31.8% (21/66) with MDS, 13.6% (9/66) with MPN, and 6% (4/66) with MPN/MDS. Clinically, of the 19 (30%) patients with prior history of cancer, 13 had treatment with chemotherapy and/or radiation. Forty-four (67%) patients had family history of cancer, with 41 including a first degree relative and 9 including a second degree relative. Breast cancer was the most common diagnosis among those with family history of cancer (12/44).
We further examined the characteristics of the TP53 mutations in our cohort. We identified that 48/66 (72.7%) cases had a single TP53 mutation of which 43 had a VAF >30% and 41 had a variant of known significance. Among the 18/66 (27.3%) cases with two TP53 mutations, 7 had a VAF >30% and all 18 had a variant of known significance. Only 1 case had a third TP53 mutation, which was a variant of known significance and had a VAF >30%. Additionally, at least one other co-mutation in a relevant gene was seen in 44% patients (29/66). Of these, the most common were DNMT3A (n=9), JAK2 (n=5), TET2 (n=5), with 3 each of BCORL1, IDH2 and NOTCH1. In terms of cytogenetics, samples were available for 60 patients of which only 4 (6.7%) had normal cytogenetics. Of those with abnormal cytogenetics, 49/56 (87.5%) had complex cytogenetics, 38/56 (67.9%) had deletion of chromosome 5q (del (5q)) and 21/56 (37.5%) had deletion of chromosome 17p (del (17p13.1)), all conferring adverse risk according to the 2017 European LeukemiaNet recommendations.
Conclusion: Despite the widespread use and availability of NGS, patients may not have clarity on the possible implications of these test results. Our cohort demonstrates that there is a significant number of MN cases that warrant further annotation to determine GL versus somatic contributions. Further identification and follow up of the GL patients will offer clarity on how these genetic risks predict future outcomes. This cohort represents work that is a stepping stone for design and justification of a future prospective study that will propose and validate criteria for GL evaluation in patients with hematological neoplasms.

Disclosures
Nazha: MEI: Consultancy. Gerds:Apexx Oncology: Consultancy; Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Carraway:Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Agios: Consultancy, Speakers Bureau.