Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in serous endometrial tumors
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually1. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology2–4.
Whole-exome sequencing was used to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 1 13 primary serous endometrial tumors. Subsequently 18 genes were resequenced, which were mutated in more than 1 1 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. High frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%) were identified. Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.
The study provides new insights into the somatic mutations present in serous endometrial cancer exomes. However, it is important to acknowledge that this discovery screen is underpowered to detect all somatically mutated genes that drive serous tumors. For example, PIK3R1, which was previously found to be somatically mutated in 8% of serous endometrial tumors58, was not somatically mutated in the tumors that formed this discovery screen.
It was estimated that, for genes that are mutated in 8% of all serous endometrial cancers, a discovery screen of 12 tumors has 25% power to detect 2 mutated tumors and 63% power to detect 1 mutated tumor; for genes that are mutated in 20% of all serous endometrial cancers, the discovery screen had an estimated 72.5% power to detect 2 mutated tumors and 93% power to detect 1 mutated tumor.
Massively parallel sequencing of additional cases will undoubtedly yield deeper insights into the mutational landscape of serous endometrial cancer. Here, it was reported one of the first exome sequencing analyses of serous endometrial cancers, which are clinically aggressive tumors that have been poorly characterized genomically.
The findings implicate the disruption of chromatin-remodeling and ubiquitin ligase complex genes in
- 50% of serous endometrial tumors and
- 35% of clear-cell endometrial tumors.
The high frequency and specific distributions of mutations in CHD4, FBXW7 and SPOP strongly suggest that these are likely to be driver events in serous endometrial cancer.
Source References:
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
zraviv06
zs22
The report lacks statistical clarity, and I am not used to the use of “power” in the way it is used. Power must mean hear that X number of cases sequenced would reveal one or more than one mutations a defined percent of the time. Power has less stress than a measure of the strength of the analysis (in prediction you would look at Akaike’s Information Criteria, Bayes Information Criteria. Given this information predication is not possible.
Now we have other information, but still lack some essentials. We have an ADDITIONAL 40 added to 111 cases (2 exclude): ALL serous type endometrial carcinoma.
Now we know that the following frequencies apply:
CHD4 17%
FBXW7 29%
SPOP 8%
These 3 are conclude to be drivers
[1] The reader is told that there are markers of chromatin remodeling and of Ubiquitone Ligase
Do all readers know which are Ch-R and which are UB Ligase?
[2] Where does the statement that these families ocuur in 50% of serous endometrial and in 35% of clear cell cases? There are no CCE adenocarcinomas in the study.
If you have only 6 markers to deal with, then what are the frequencies of pairs of the 3 drivers in binary combination.
If you have 3 predictors that can be assigned either 0 or 1, then a Bernoulli trial would give
000 12.5
010 12.5
100 12.5
001 12.5
110 12.5
101 12.5
011 12.5
111 12.5
NO SERIOUS anomaly
000 16.5
010 8.0
100 8.2
001 8.0
110 14.0
101 17.8
011 15.5
111 21.5
Strong information.
There is another permutation of this that I haven’t done. You have say 2 other predictors that are weak. You might assign a 0 or 1 if either is neg/pos. I’m not inclined to use 0,1,2., confusing the matter.
The Bernoulli trial 2 would go to a 4 letter code with
0000
1000
0100
0010
0001
0011
0110
1100
1010
0101
1001
0111
1011
1110
1101
1111
1101
2*4 16 theoretical classes
equal distribution is at maximum entropy!
Information is present with a drop in entropy based on differences in the distribution of classes.
Dr. Saha, I think that the analysis of power is critical to these type of studies. The mutation in PI3KCA is well known and there are PI3KCA mutant GEM models of endometrial cancer that have been developed. It may appear that the drivers of oncogenesis may actually be the low frequency mutations and that you would need an extraordinary number of tumors to detect this. However this would make an interesting point. How do we extend this to personalized medicine? Would we need to sequence a patients tumor DNA from over 112 biopsies of the same patient just to detect these low frequency (but maybe more relevant) mutations?
Dr. Saha,
Thank you for this post.
Please write another post on finding for
mutations in chromatin-remodeling and ubiquitin ligase complex genes in Breast Cancer
Thank you
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.