Outcomes with lower intensity therapy in TP53-mutated AML.

7017 Background: TP53 mutations confer an adverse prognosis in patients (pts) with AML treated with standard chemotherapy. A recent study reported high response rates using a 10-day regimen of decitabine (DAC10) in pts with TP53-mutated ( TP53-MUT) AML. The question remains whether this benefit is unique to DAC10 or whether the same benefit among TP53-MUT AML applies to other low intensity therapy (Rx). Methods: We reviewed our own experience of pts treated with low intensity Rx from 2012 - 2016. Mutation testing was performed using a whole-exome sequencing panel. We reviewed the clinico-pathologic characteristics of these pts, and compared their outcomes based on the presence/absence of a TP53mutation and by the type of Rx they received. Results: There were 131 pts in our cohort of which 33 (25%) had TP53-MUT. Pt characteristics are outlined in Table 1A. All pts were treated with low intensity Rx and were divided into the following groups: DAC10 [n=34, 26%]; 5-day decitabine, or 7-day azacytidine (DAC5) [n=39, 30%]; or cladribine+low dose araC (CLAD/LDAC) [n=58, 44%]. Response rates and OS by Rx and TP53-MUT status are summarized in Table 1B. While there was no significant difference in response rates or OS by TP53-MUT status within any of the treatment approaches, there was a trend for inferior response rates and OS among pts with TP53-MUT who received either DAC-5 or CLAD/LDAC ; this was not seen in pts receiving DAC10. Conclusions: The presence of a TP53-MUT was associated with a nonsignificant trend towards inferior outcomes among pts receiving DAC5 or CLAD/LDAC, but not among those receiving DAC10. Comparing across groups, the CLAD/LDAC combination was associated with the longest OS, and DAC10 was associated with superior outcomes compared to DAC5, in TP53-MUT cohort. [Table: see text]

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Cancer-Specific Thresholds Adjust for Whole Exome Sequencing–Based Tumor Mutational Burden Distribution

JCO Precision Oncology ◽

10.1200/po.18.00400 ◽

2019 ◽

pp. 1-12

Author(s):

Evan M. Fernandez ◽

Kenneth Eng ◽

Shaham Beg ◽

Himisha Beltran ◽

Bishoy M. Faltas ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Disease Stage ◽

Cancer Type ◽

Primary Tumors ◽

Mutational Burden ◽

Whole Exome ◽

Significant Difference ◽

Tumor Mutational Burden ◽

Pan Cancer

PURPOSE To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. MATERIALS AND METHODS Using whole exome sequencing data from primary tumors in The Cancer Genome Atlas (n = 3,534) and advanced and/or metastatic tumors from Weill Cornell Medicine Advanced (n = 696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. RESULTS The distribution of TMB varied dramatically among cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, whereas the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared with the static pan-cancer threshold. In addition, no significant difference in survival outcomes was found with the cancer-specific threshold compared with the pan-cancer threshold. Furthermore, the cancer-specific threshold maintained higher predicted neoantigen load for the TMB-high samples compared with the TMB-low samples, even when the threshold was lower than the pan-cancer threshold. CONCLUSION TMB is determined within the context of cancer type, metastatic state, and disease stage. Compared with a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that are not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Because of the potential impact in the care of patients with cancer, TMB status should be determined in a cancer-specific manner.

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Profile of genetic variations in severely calcified carotid plaques by whole-exome sequencing

Surgical Neurology International ◽

10.25259/sni_387_2020 ◽

2020 ◽

Vol 11 ◽

pp. 286

Author(s):

Hiroyuki Katano ◽

Yusuke Nishikawa ◽

Hiroshi Yamada ◽

Takashi Iwata ◽

Mitsuhito Mase

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Base Pair ◽

Genetic Variants ◽

Bioinformatic Analysis ◽

Specific Gene ◽

Carotid Plaques ◽

Vascular Regulation ◽

Whole Exome ◽

Significant Difference

Background: The precise mechanisms of carotid calcification and its clinical significance have not been established. Methods: We classified ten plaques from carotid endarterectomy patients into high- and low-calcified plaques based on the Agatston calcium scores. We performed whole-exome sequencing for genetic profiles with single nucleotide variations (SNVs), insertions, and deletions. Bioinformatic data mining was then conducted to disclose specific gene variations to either high- or low-calcified carotid plaques. Results: In the carotid plaques, G:C>A:T/C:G>T:A transitions as SNVs, insT after C/insC after A as insertions, and delA after G/delT after C as deletions were most frequently observed, but no significant difference was observed between the high- and low-calcified plaque groups in their proportion of base-pair substitution types. In the bioinformatic analysis, SNVs of ATP binding cassette subfamily C member 6 (ADCC6) were more commonly found in high-calcified plaques and SNVs of KLKB1 were more commonly found in low-calcified plaques compared to the other group. No new genetic variants related to calcification or atherosclerosis among those not registered in dbSNP was detected. Conclusion: Our findings clarified the features of base-pair substitutions in carotid plaques, showing no relation to calcification. However, genetic variants in ADCC6 relating to vascular calcification for high-calcified plaques, and in KLKB1 encoding kallikrein associated with vascular regulation of atherosclerosis for low-calcified plaques were more specifically extracted. These results contribute to a better understanding of the genetic basis of molecular activity and calcium formation in carotid plaques.

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Identifying the causes of recurrent pregnancy loss in consanguineous couples using whole exome sequencing on the products of miscarriage with no chromosomal abnormalities

Scientific Reports ◽

10.1038/s41598-021-86309-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kimia Najafi ◽

Zohreh Mehrjoo ◽

Fariba Ardalani ◽

Siavash Ghaderi-Sohi ◽

Ariana Kariminejad ◽

...

Keyword(s):

Genetic Testing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chromosomal Abnormalities ◽

Comparative Genomic ◽

Iranian Women ◽

Recurrent Miscarriages ◽

Consanguineous Marriages ◽

Whole Exome ◽

Significant Difference

AbstractRecurrent miscarriages occur in about 5% of couples trying to conceive. In the past decade, the products of miscarriage have been studied using array comparative genomic hybridization (a-CGH). Within the last decade, an association has been proposed between miscarriages and single or multigenic changes, introducing the possibility of detecting other underlying genetic factors by whole exome sequencing (WES). We performed a-CGH on the products of miscarriage from 1625 Iranian women in consanguineous or non-consanguineous marriages. WES was carried out on DNA extracted from the products of miscarriage from 20 Iranian women in consanguineous marriages and with earlier normal genetic testing. Using a-CGH, a statistically significant difference was detected between the frequency of imbalances in related vs. unrelated couples (P < 0.001). WES positively identified relevant alterations in 11 genes in 65% of cases. In 45% of cases, we were able to classify these variants as pathogenic or likely pathogenic, according to the American College of Medical Genetics and Genomics guidelines, while in the remainder, the variants were classified as of unknown significance. To the best of our knowledge, our study is the first to employ WES on the products of miscarriage in consanguineous families with recurrent miscarriages regardless of the presence of fetal abnormalities. We propose that WES can be helpful in making a diagnosis of lethal disorders in consanguineous couples after prior genetic testing.

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