BACKGROUND Cyclin-dependent kinase inhibitor 1C(CDKN1C)is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest.CDKN1C mutations can lead to IMAGe syndrome(CDKN1C al...BACKGROUND Cyclin-dependent kinase inhibitor 1C(CDKN1C)is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest.CDKN1C mutations can lead to IMAGe syndrome(CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction,metaphyseal dysplasia,adrenal hypoplasia congenital,and genitourinary malformations).We present a Silver-Russell syndrome(SRS)pedigree that was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency.The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.CASE SUMMARY We describe the case of an 8-year-old girl who initially presented with short stature.Her height was 91.6 cm,and her weight was 10.2 kg.Physical examination revealed that she had a relatively large head,an inverted triangular face,a protruding forehead,a low ear position,sunken eye sockets,and irregular cracked teeth but no limb asymmetry.Family history:The girl’s mother,greatgrandmother,and grandmother’s brother also had a prominent forehead,triangular face,and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency.Exome sequencing of the girl revealed a new heterozygous CDKN1C(NM_000076.2)c.836G>A mutation,resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine(p.Arg279His).The same causative mutation was found in both the proband’s mother,great-grandmother,and grandmother’s brother,who had similar phenotypes.Thus far,we found an SRS pedigree,which was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region[the proliferating cell nuclear antigen(PCNA)domain],no adrenal insufficiency was reported in this SRS pedigree.The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype.The proband was treated with recombinant human growth hormone(rhGH).After 1 year of rhGH treatment,the height standard deviation score of the proband increased by 0.93 standard deviation score,and her growth rate was 8.1 cm/year.No adverse reactions,such as abnormal blood glucose,were found.CONCLUSION Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry,and some patients may have glucose abnormalities.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.展开更多
MEK1/2 inhibitors are clinically approved for the treatment of BRAF-mutant melanoma,where they are used in combination with BRAF inhibitors,and are undergoing evaluation in other malignancies.Acquired resistance to ME...MEK1/2 inhibitors are clinically approved for the treatment of BRAF-mutant melanoma,where they are used in combination with BRAF inhibitors,and are undergoing evaluation in other malignancies.Acquired resistance to MEK1/2 inhibitors,including selumetinib(AZD6244/ARRY-142866),can arise through amplification of BRAF^(V600E) or KRAS^(G13D) to reinstate ERK1/2 signalling.We have found that BRAF^(V600E) amplification and selumetinib resistance are fully reversible following drug withdrawal.This is because resistant cells with BRAF^(V600E) amplification become addicted to selumetinib to maintain a precise level of ERK1/2 signalling(2%-3%of total ERK1/2 active),that is optimal for cell proliferation and survival.Selumetinib withdrawal drives ERK1/2 activation outside of this critical“sweet spot”(~20%-30%of ERK1/2 active)resulting in a p57^(KIP2)-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death with features of autophagy;these terminal responses select against cells with amplified BRAF^(V600E).ERK1/2-dependent p57^(KIP2) expression is required for loss of BRAF^(V600E) amplification and determines the rate of reversal of selumetinib resistance.Growth of selumetinib-resistant cells with BRAF^(V600E) amplification as tumour xenografts also requires the presence of selumetinib to“clamp”ERK1/2 activity within the sweet spot.Thus,BRAF^(V600E) amplification confers a selective disadvantage or“fitness deficit”during drug withdrawal,providing a rationale for intermittent dosing to forestall resistance.Remarkably,selumetinib resistance driven by KRAS^(G13D) amplification/upregulation is not reversible.In these cells ERK1/2 reactivation does not inhibit proliferation but drives a ZEB1-dependent epithelial-to-mesenchymal transition that increases cell motility and promotes resistance to traditional chemotherapy agents.Our results reveal that the emergence of drug-addicted,MEKi-resistant cells,and the opportunity this may afford for intermittent dosing schedules(“drug holidays”),may be determined by the nature of the amplified driving oncogene(BRAF^(V600E) vs.KRAS^(G13D)),further exemplifying the difficulties of targeting KRAS mutant tumour cells.展开更多
基金supported by grants from The National Natural Science Foundation of China(31260271)The Natural Science Foundation of Inner Mongolia,China(2012MS0513)
基金Supported by the China Foundation for International Medical Exchange,Pediatric Endocrinology Young and Middle-Aged Doctors’Growth Research Fund,No.Z-2019-41-2101-01.
文摘BACKGROUND Cyclin-dependent kinase inhibitor 1C(CDKN1C)is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest.CDKN1C mutations can lead to IMAGe syndrome(CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction,metaphyseal dysplasia,adrenal hypoplasia congenital,and genitourinary malformations).We present a Silver-Russell syndrome(SRS)pedigree that was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency.The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.CASE SUMMARY We describe the case of an 8-year-old girl who initially presented with short stature.Her height was 91.6 cm,and her weight was 10.2 kg.Physical examination revealed that she had a relatively large head,an inverted triangular face,a protruding forehead,a low ear position,sunken eye sockets,and irregular cracked teeth but no limb asymmetry.Family history:The girl’s mother,greatgrandmother,and grandmother’s brother also had a prominent forehead,triangular face,and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency.Exome sequencing of the girl revealed a new heterozygous CDKN1C(NM_000076.2)c.836G>A mutation,resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine(p.Arg279His).The same causative mutation was found in both the proband’s mother,great-grandmother,and grandmother’s brother,who had similar phenotypes.Thus far,we found an SRS pedigree,which was due to a missense mutation affecting the same amino acid position,279,in the CDKN1C gene,resulting in the amino acid substitution p.Arg279His(c.836G>A).Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region[the proliferating cell nuclear antigen(PCNA)domain],no adrenal insufficiency was reported in this SRS pedigree.The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype.The proband was treated with recombinant human growth hormone(rhGH).After 1 year of rhGH treatment,the height standard deviation score of the proband increased by 0.93 standard deviation score,and her growth rate was 8.1 cm/year.No adverse reactions,such as abnormal blood glucose,were found.CONCLUSION Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry,and some patients may have glucose abnormalities.In familial SRS patients,the PCNA region of CDKN1C should be analysed.Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.
基金Work in the Cook laboratory relevant to this article was supported by Cancer Research UK A14867,a Cambridge Cancer Centre PhD Studentship,a BBSRC PhD studentship,to Sale MJ and Cook SJan AstraZeneca-Cambridge Cancer Centre Collaborative Award,to Sale MJ and Cook SJInstitute Strategic Programme(BB/J004456/1,BB/P013384/1)from BBSRC to Balmanno K and Cook SJ,and AstraZeneca.
文摘MEK1/2 inhibitors are clinically approved for the treatment of BRAF-mutant melanoma,where they are used in combination with BRAF inhibitors,and are undergoing evaluation in other malignancies.Acquired resistance to MEK1/2 inhibitors,including selumetinib(AZD6244/ARRY-142866),can arise through amplification of BRAF^(V600E) or KRAS^(G13D) to reinstate ERK1/2 signalling.We have found that BRAF^(V600E) amplification and selumetinib resistance are fully reversible following drug withdrawal.This is because resistant cells with BRAF^(V600E) amplification become addicted to selumetinib to maintain a precise level of ERK1/2 signalling(2%-3%of total ERK1/2 active),that is optimal for cell proliferation and survival.Selumetinib withdrawal drives ERK1/2 activation outside of this critical“sweet spot”(~20%-30%of ERK1/2 active)resulting in a p57^(KIP2)-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death with features of autophagy;these terminal responses select against cells with amplified BRAF^(V600E).ERK1/2-dependent p57^(KIP2) expression is required for loss of BRAF^(V600E) amplification and determines the rate of reversal of selumetinib resistance.Growth of selumetinib-resistant cells with BRAF^(V600E) amplification as tumour xenografts also requires the presence of selumetinib to“clamp”ERK1/2 activity within the sweet spot.Thus,BRAF^(V600E) amplification confers a selective disadvantage or“fitness deficit”during drug withdrawal,providing a rationale for intermittent dosing to forestall resistance.Remarkably,selumetinib resistance driven by KRAS^(G13D) amplification/upregulation is not reversible.In these cells ERK1/2 reactivation does not inhibit proliferation but drives a ZEB1-dependent epithelial-to-mesenchymal transition that increases cell motility and promotes resistance to traditional chemotherapy agents.Our results reveal that the emergence of drug-addicted,MEKi-resistant cells,and the opportunity this may afford for intermittent dosing schedules(“drug holidays”),may be determined by the nature of the amplified driving oncogene(BRAF^(V600E) vs.KRAS^(G13D)),further exemplifying the difficulties of targeting KRAS mutant tumour cells.
