Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy

Purpose: Evaluate response of mismatch repair deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty dMMR rectal cancer patients were identified by immunohistochemistry and/or microsatellite instability analysis, with initial treatment response compared to a matched pMMR rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), 6 (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable to 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome (LS) with enrichment of germline MSH2 and MSH6 mutations when compared to 193 LS-associated colon cancer patients (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < .003). Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for LS in dMMR rectal cancer patients

A record on benthic foraminiferal abundance and distribution in Gosthani estuary, Bheemunipatnam, Andhra Pradesh.

425-429A total of 482 Benthic foraminifera belonging to 23 species have been identified in the sediment samples of Gosthani estuary. The Ammonia beccarii, Anomalina sp., Asterorotalia dentata, Ammonia tepida, Quinquloculina seminulum, Asterorotalia trispinosa, and<i style="mso-bidi-font-style: normal"> Elphidium crispum are abundant<i style="mso-bidi-font-style: normal">. Anomalina sp., represent the shelf environment and it is a good indication of flooding or marine water incursion into the estuary. Q-mode cluster analysis revealed that the foraminifera could be grouped into 6 clusters. Occurrence and distribution of foraminiferal assemblages studied in the Gosthani estuary sediments, infers that these sediments were deposited in marine environment. </span

Total synthesis of (−)-Sachalinol A and evaluation of its cytotoxicity

695-700(-)-Sachalinol A, a group of monoterpenoids, oxygenated derivatives of rosinidol, has been synthesized employing a simple, eight step procedure. The compound demonstrates excellent cytotoxicity against MDA-MB-231 derived from human breast adenocarcinoma cells (ATCC No. HTB-26) and HeLa derived from human cervical cancer cells (ATCC No. CCL-2). Good activity is observed against A549 derived from human alveolar adenocarcinoma epithelial cells (ATCC No. CCL-185) and Neuro2a derived from mouse neuroblastoma cells (ATCC No. CCL-131). Moderate activity is also observed against MCF-7 derived from human breast adenocarcinoma cells (ATCC No. HTB-22)

Structural and mutational analysis reveals that CTNNBL1 binds NLSs in a manner distinct from that of its closest armadillo-relative, karyopherin α

AbstractCTNNBL1 is a spliceosome-associated protein that binds nuclear localization signals (NLSs) in splice factors CDC5L and Prp31 as well as the antibody diversifying enzyme AID. Here, crystal structures of human CTNNBL1 reveal a distinct structure from its closest homologue karyopherin-α. CTNNBL1 comprises a HEAT-like domain (including a nuclear export signal), a central armadillo domain, and a coiled-coil C-terminal domain. Structure-guided mutations of the region homologous to the karyopherin-α NLS-binding site fail to disrupt CTNNBL1–NLS interactions. Our results identify CTNNBL1 as a unique selective NLS-binding protein with striking differences from karyopherin-αs

CTNNBL1 Is a Novel Nuclear Localization Sequence-binding Protein That Recognizes RNA-splicing Factors CDC5L and Prp31

Nuclear proteins typically contain short stretches of basic amino acids (nuclear localization sequences; NLSs) that bind karyopherin α family members, directing nuclear import. Here, we identify CTNNBL1 (catenin-β-like 1), an armadillo motif-containing nuclear protein that exhibits no detectable primary sequence homology to karyopherin α, as a novel, selective NLS-binding protein. CTNNBL1 (a single-copy gene conserved from fission yeast to man) was previously found associated with Prp19-containing RNA-splicing complexes as well as with the antibody-diversifying enzyme AID. We find that CTNNBL1 association with the Prp19 complex is mediated by recognition of the NLS of the CDC5L component of the complex and show that CTNNBL1 also interacts with Prp31 (another U4/U6.U5 tri-snRNP-associated splicing factor) through its NLS. As with karyopherin αs, CTNNBL1 binds NLSs via its armadillo (ARM) domain, but displays a separate, more selective NLS binding specificity. Furthermore, the CTNNBL1/AID interaction depends on amino acids forming the AID conformational NLS with CTNNBL1-deficient cells showing a partial defect in AID nuclear accumulation. However, in further contrast to karyopherin αs, the CTNNBL1 N-terminal region itself binds karyopherin αs (rather than karyopherin β), suggesting a function divergent from canonical nuclear transport. Thus, CTNNBL1 is a novel NLS-binding protein, distinct from karyopherin αs, with the results suggesting a possible role in the selective intranuclear targeting or interactions of some splicing-associated complexes

Abstract 5747: Chemotherapy-related mutational signatures reveal the origins of therapy-related myeloid neoplasms

Abstract Patients treated with chemotherapy (CT) and/or autologous stem-cell transplantation (ASCT) are at risk for therapy-related myeloid neoplasms (tMN). Certain cytotoxic agents introduce mutations within distinct trinucleotide contexts resulting in a unique barcode for each exposed cell. We leveraged mutational signatures to investigate the role of CT in the genomic landscape of tMN with respect to antecedent clonal hematopoiesis (CH). We analyzed 32 tMN and 2 tALL from 33 patients and interrogated for copy number abnormalities (CNA), structural variants (SV), single nucleotide variants (SNV), and mutational signatures. For 7 patients with tMN post-melphalan/ASCT, we investigated antecedent CH using targeted sequencing on pre-melphalan samples, including autograft products. CH variants that became clonal in tumor were seen in 5/7 pre-melphalan/ASCT samples (TP53, RUNX1, NCOR1, NF1, CREBBP, DNMT3A, and PPM1D). Complex SV were seen in 7 tMNs; including chromothripsis in 6 (19.4%). In 4 cases, chromothripsis involved chromosome 19 with hyper-amplification of the SMARCA4 locus (≥5 copies). Mutational signature analysis revealed 6 known single base substitution (SBS) signatures in tMN including melphalan (SBS-MM1) and platinum signatures (SBS31, SBS35, and E-SBS37). TMNs with CT signatures had higher mutation burden than those without (p = 0.004). 17 patients with exposure to agents other than melphalan/platinum did not have increased mutational burden with respect to de novo AML (TCGA; NEJM, 2013). All patients with prior platinum exposure (including tALL, n=9) had platinum SBS signatures while only 2 of 7 patients with prior melphalan/ASCT had a melphalan signature (SBS-MM1). Detection of CT signatures in bulk sequencing relies on one cell, with its barcode of mutations, to expand to clonal dominance. Given pre-existent CH, including in 3/3 autograft products, absence of a CT signature despite melphalan exposure implies progression by a clone that escaped CT exposure with stem-cell collection and reinfusion. Conversely, all platinum-exposed tAML had signature evidence of exposure confirming existence of CH prior to exposure and supporting post-CT single-cell expansion. TMNs from 3 patients exposed to sequential platinum and melphalan/ASCT had platinum but not melphalan signatures confirming single-cell expansion of the pre-tMN CH clone post-platinum but with escape from exposure to melphalan via leukapheresis. Chromothripsis events bore only non-duplicated CT-induced mutations, indicative of acquisition prior to, and not directly caused by, CT exposure. These disparities suggest that ASCT provides a mechanism for CH clones to escape CT and re-engraft with transplant. Coupled with driver events accrued prior to CT, this suggest that CT-induced mutagenesis may be less important than other factors, such as CT-induced immunosuppression, in the expansion of pre-TMN CH clones. Citation Format: Benjamin Diamond, Bachisio Ziccheddu, Eileen M. Boyle, Kylee Maclachlan, Justin Taylor, Justin M. Watts, Sydney X. Lu, David G. Coffey, Niccolo Bolli, Elli Papaemmanuil, Kelly Bolton, Jae H. Park, Heather Landau, Karuna Ganesh, Mikkael A. Sekeres, Stephen Nimer, David J. Chung, Caleb H. Ho, Mikhail Roshal, Alexander Lesokhin, Gareth Morgan, Ola Landgren, Francesco Maura. Chemotherapy-related mutational signatures reveal the origins of therapy-related myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5747