scholarly journals gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans.

Genetics ◽  
1995 ◽  
Vol 139 (2) ◽  
pp. 579-606 ◽  
Author(s):  
R Francis ◽  
M K Barton ◽  
J Kimble ◽  
T Schedl
Keyword(s):  
Caenorhabditis Elegans ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Germ Cells ◽  
Meiotic Prophase ◽  
Suppressor Gene ◽  
Oocyte Development ◽  
Loss Of Function ◽  
Germline Development ◽  
Germline Sex Determination

Abstract We have characterized 31 mutations in the gld-1 (defective in germline development) gene of Caenorhabditis elegans. In gld-1 (null) hermaphrodites, oogenesis is abolished and a germline tumor forms where oocyte development would normally occur. By contrast, gld-1 (null) males are unaffected. The hermaphrodite germline tumor appears to derive from germ cells that enter the meiotic pathway normally but then exit pachytene and return to the mitotic cycle. Certain gld-1 partial loss-of-function mutations also abolish oogenesis, but germ cells arrest in pachytene rather than returning to mitosis. Our results indicate that gld-1 is a tumor suppressor gene required for oocyte development. The tumorous phenotype suggests that gld-1(+) may function to negatively regulate proliferation during meiotic prophase and/or act to direct progression through meiotic prophase. We also show that gld-1(+) has an additional nonessential role in germline sex determination: promotion of hermaphrodite spermatogenesis. This function of gld-1 is inferred from a haplo-insufficient phenotype and from the properties of gain-of-function gld-1 mutations that cause alterations in the sexual identity of germ cells.

Genetic relationship between pilar cysts, pilar tumors and pilar carcinomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21063-e21063
Author(s):  
Rachael Hagen ◽  
Joanna Amy Kolodney ◽  
Jessica Patterson ◽  
Michael Kolodney
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Somatic Mutation ◽  
Autosomal Dominant ◽  
Genetic Relationships ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Whole Exome ◽  
The Subject ◽  
Autosomal Dominant Inheritance Pattern

e21063 Background: Pilar cysts, also known as trichilemmal cysts, are common cutaneous nodules that occur sporadically or an autosomal dominant inheritance pattern. A pilar cyst can transform into a proliferating pilar tumor (PPT) or pilar carcinoma. This study aimed to determine the genetic relationships between the malignant variants and the precursor pilar cysts. Methods: We performed whole exome (WES) and Sanger sequencing of pilar cysts and matched blood (or other non-lesional tissue representing systemic DNA) from 17 subjects with multiple familial pilar cysts and 15 with a single, apparently sporadic, pilar cyst. We then performed WES on four subjects with PPTs, one with matched blood, and one subject with a pilar carcinoma matched with blood. Results: We identified a c.2234G > A somatic mutation in phospholipase C delta 1 ( PLCD1), a tumor suppressor gene, in all 21 familial pilar cysts sequenced. In addition, 16 of the 17 subjects with familial pilar cysts were hemizygous for a c.1379G > A germline variant in PLCD1. By contrast, neither of these two mutations were found in subjects with PPTs or the subject with a pilar carcinoma. A potential loss-of-function somatic mutation of the tumor suppressor gene p53 was identified in the subject with a pilar carcinoma. Conclusions: Our results indicate that hereditary pilar cysts are an autosomal dominant tumor syndrome resulting from two hits to the PLCD1 tumor suppressor gene. However, these somatic PLCD1 mutations were not present in the four PPTs or the pilar carcinoma. This suggests that the more aggressive cyst variants originate from sporadic pilar cysts. In addition, our results are consistent with loss of p53 being a key event that causes pilar cysts to evolve into carcinomas as previously proposed.

ALK resistance mutations (muts) developed in different ALK fusion types.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14741-e14741
Author(s):  
Jun Zhao ◽  
Caixia Liu ◽  
Jianhua Chen ◽  
Likun Chen ◽  
Xinghao Ai ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Gene ◽  
Resistance Mechanisms ◽  
Kinase Domain ◽  
Loss Of Function ◽  
Resistance Mutations ◽  
Alk Inhibitors ◽  
Fusion Type

e14741 Background: Patients (pts) treated with ALK inhibitors (ALKi) inevitably develops resistance. Diverse mutations (muts) confer resistance to ALKis, which may be related to the diverse types of ALK fusion. The objective of this study is to see whether the resistance mechanisms developed during ALKi therapy are ALK fusion types dependent. Methods: The mutation profiles of 38 pts with known ALK fusion partners and positions, who ordered NGS test in our institution after progressed on ≥ 1 ALKis, were analyzed. Results: Resistant muts in ALK kinase domain ( ALK resistant muts) were detected in 53% (20/38) of the resistant pts. 100% (1/1) of the EML4-ALK V5’ variant (V5’), 81% (13/16) of the EML4-ALK V3 variant (V3), 60% (3/5) of the non- EML4-ALK, 23% (3/13) of EML4-ALK V1 variant (V1), and 0% (0/3) of the EML4-ALK V2 variant (V2) had ALK resistant muts. ALK G1202R was detected in 29% of the pts. 100% (1/1) of the V5’, 50% (8/16) of the V3, 20% (1/5, HIP1-ALK) of the non- EML4-ALK, and none of the V1 (0/13) and V2 (0/3) had G1202R. Amplification and gain of function muts in oncogenes and loss of function muts in tumor suppressor gene were detected in 16% (6/38) of the pts, namely 4 V1, 1 V2, and 1 V3. On average, pts treated with 3rd generation ALKis had significantly more muts in ALK (7.5 vs. 3.6, p = 0.0008) and in all targeted regions (9.1 vs. 4.3, p = 0.0005) than pts treated with only 1st and 2nd generation ALKis. Conclusions: The type of resistance mechanisms developed during ALKi therapy may depend on the ALK fusion type of the pt. ALK resistant muts, especially G1202R, developed most frequently in V3/V5’, followed by non- EML4-ALK, and V1/V2, while amplification and grain of function muts in oncogenes and loss of function muts in tumor suppressor genes developed more often in V1/V2 than in V3/V5’. The 3rd generation ALKi may increase the genomic alterations in treated pts.

scholarly journals hH-Rev107, a class II tumor suppressor gene, is expressed by post-meiotic testicular germ cells and CIS cells but not by human testicular germ cell tumors

Oncogene ◽  
2001 ◽  
Vol 20 (37) ◽  
pp. 5155-5163 ◽  
Author(s):  
Sylvie Siegrist ◽  
Chloé Féral ◽  
Mounia Chami ◽  
Brigitte Solhonne ◽  
Marie-Geneviève Mattéi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Germ Cell ◽  
Tumor Suppressor Gene ◽  
Germ Cells ◽  
Germ Cell Tumors ◽  
Class Ii ◽  
Suppressor Gene ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell

scholarly journals The mog-1 gene is required for the switch from spermatogenesis to oogenesis in Caenorhabditis elegans.

Genetics ◽  
1993 ◽  
Vol 133 (4) ◽  
pp. 919-931 ◽  
Author(s):  
P L Graham ◽  
J Kimble
Keyword(s):  
Caenorhabditis Elegans ◽  
Sex Determination ◽  
Germ Cells ◽  
Germ Line ◽  
Loss Of Function ◽  
Wild Type ◽  
Per Se ◽  
Post Transcriptional Regulation ◽  
Germline Sex Determination ◽  
Embryonic Death

Abstract Caenorhabditis elegans hermaphrodites make first sperm, then oocytes. By contrast, animals homozygous for any of six loss-of-function mutations in the gene mog-1 (for masculinization of the germ line) make sperm continuously and do not switch into oogenesis. Therefore, in mog-1 mutants, germ cells that normally would become oocytes are transformed into sperm. By contrast, somatic sexual fates are normal, suggesting that mog-1 plays a germ line-specific role in sex determination. Analyses of double mutants suggest that mog-1 negatively regulates the fem genes and/or fog-1: mog-1; fem and mog-1; fog-1 double mutants all make oocytes rather than sperm. Therefore, we propose that wild-type mog-1 is required in the hermaphrodite germ line for regulation of the switch from spermatogenesis to oogenesis rather than for specification of oogenesis per se. In addition to its role in germline sex determination, maternal mog-1 is required for embryogenesis: most progeny of a mog-1; fem or mog-1; fog-1 mother die as embryos. How might the roles of mog-1 in the sperm/oocyte switch and embryogenesis be linked? Previous work showed that fem-3 is regulated post-transcriptionally to achieve the sperm/oocyte switch. We speculate that mog-1 may function in the post-transcriptional regulation of numerous germ-line RNAs, including fem-3. A loss of mog-1 might inappropriately activate fem-3 and thereby abolish the sperm/oocyte switch; its loss might also lead to misregulation of maternal RNAs and thus embryonic death.

scholarly journals FHITDoubts are Clear Now

2010 ◽  
Vol 10 ◽  
pp. 1142-1151 ◽  
Author(s):  
Anjilna Wali
Keyword(s):  
Tumor Suppressor ◽  
Cell Line ◽  
Tumor Suppressor Gene ◽  
Promoter Region ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Chromosome 3 ◽  
Loss Of Function ◽  
Methylation Analysis ◽  
Different Types

The fragile histidine triad (FHIT) gene is a bonafide tumor-suppressor gene present on the short arm of chromosome 3 and its loss of function has been evaluated in different types of cancers. Loss of heterozygosity at various sections of theFHITgene and the methylation analysis of the promoter region showed that it is one of the important and preliminary genetic alterations in the cell, and its restoration in the cell line or nude mice suppresses tumorigenicity. Current research on theFHITgene has depicted that Fhit interacts with different proteins through different pathways in the nucleus, mitochondria, and cytoplasm, directing the cell to apoptosis.

Loss-Of-Function Mutation Of ARID1A Tumor Suppressor Gene In A Glycogen-Rich Clear Cell Mammary Carcinoma

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S146-S146
Author(s):  
C A De la Sancha Verduzco ◽  
N Popnikolov ◽  
R Ruiz-Cordero
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Molecular Mechanisms ◽  
Clear Cell ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Chromosome 1 ◽  
Loss Of Function ◽  
Truncating Mutation ◽  
Molecular Studies

Abstract Introduction/Objective Glycogen-rich clear cell carcinoma (GRCC-CA) is a rare subtype of breast carcinoma accounting for 0.9 - 3% of all breast malignancies. It is characterized by more than 90% of the neoplastic cells containing glycogen-abundant clear cytoplasm. Due to the rarity of this tumor, the information about the specific genetic alterations, their prognostic significance and potential therapeutic implications are quite limited. Here we report the molecular alterations of a GRCC-CA diagnosed in a 69-year-old woman. Methods Tumor-only sequencing using a hybrid-capture next-generation sequencing (HC-NGS) assay was performed using formalin-fixed paraffin-embedded tissue. The HC-NGS panel included the coding regions of 479 cancer-related genes, select introns of 47 genes and the TERT promoter. Results The HC-NGS showed the following alterations: 1) large inversion in chromosome 1 between exon 20 of gene ARID1A (1p36.12) and intron 2 of KDM5B (1q32.1) leading to loss-of-function of ARID1A tumor suppressor gene, 2) MAP2K4 p.E376 truncating mutation with a variant allelic frequency of 87% suggestive of loss-of-heterozygosity, 3) c- MYC gene amplification (5x), 4) variant of uncertain significance in gene PTPRB (p.D1848N) and 5) deep deletions of NCKAP5, CCNT2, MAP3K19, LRP1B, and KMT2A genes. Conclusion We report for the first time a loss-of-function mutation of ARID1A gene in mammary GRCC-CA. Loss of function of ARID1A gene, as shown by molecular studies or loss of protein expression, is often seen in clear cell carcinomas with high glycogen contents from other sites (ovary and kidney), indicating similarities in the molecular mechanisms of development. In our patient, the loss of ARID1A probably enhanced the effect of the c-MYC amplification, since ARID1A is involved in the repression of c-MYC and other proliferation associated genes during differentiation. Larger molecular studies are needed to elucidate further the genetic mechanisms of mammary GRCC- CA.

scholarly journals Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/−clear cell renal carcinoma

2017 ◽  
Vol 114 (5) ◽  
pp. 1027-1032 ◽  
Author(s):  
Wenhua Gao ◽  
Wei Li ◽  
Tengfei Xiao ◽  
Xiaole Shirley Liu ◽  
William G. Kaelin
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Target Genes ◽  
Clear Cell ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Renal Carcinogenesis ◽  
Transcriptional Signature

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of theVHLtumor suppressor gene. TheVHLgene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of thePBRM1andBAP1tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC.PBRM1encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature.

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