Non-hotspot PIK3CA mutations are more frequent in CLOVES than in common or combined lymphatic malformations.
Non-hotspot PIK3CA mutations are more frequent in CLOVES than in common or combined lymphatic malformations.
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DOI：
10.1186/s13023-021-01898-y
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发表时间：
2021-06-10
影响因子：
3.7
通讯作者：
Vikkula M
中科院分区：
文献类型：
--
作者：
Brouillard P;Schlögel MJ;Homayun Sepehr N;Helaers R;Queisser A;Fastré E;Boutry S;Schmitz S;Clapuyt P;Hammer F;Dompmartin A;Weitz-Tuoretmaa A;Laranne J;Pasquesoone L;Vilain C;Boon LM;Vikkula M
诊断管理，根据精确的病理分子靶点进行治疗，要求解开患者的基因型。我们使用靶向下一代测序（NGS）或数字液滴聚合酶链反应（ddPCR）筛选从切除的病变组织或从病变分离的淋巴内皮细胞（LECs）中提取的DNA上的体细胞PIK3CA突变。我们的队列（n = 143）由患有常见淋巴畸形（LM），合并淋巴畸形[淋巴-静脉畸形（LVM），毛细血管-淋巴畸形（CLM），毛细血管-淋巴-静脉畸形（CLVM）]或综合征[CLVM合并肥大（klippel - trenauny - weber综合征，KTS），先天性脂肪瘤过度生长-血管畸形-表皮痣综合征（CLOVES）]的无关患者组成。未分类的pik3ca相关过度生长综合征（PROS）或未分类的血管（淋巴）异常综合征（UVA）]。我们在143例患者中发现108例（75.5%）的切除病变中存在体细胞PIK3CA突变。变异等位基因在组织中的频率从0.54到25.33%不等，在分离的内皮细胞中高达47%。我们发现，与综合征相比，普通LM和合并LM患者的突变分布在统计学上有显著差异，但与KTS相比没有统计学差异。此外，变异等位基因频率在综合征中较高。大多数患有常见或合并淋巴畸形（伴或不伴过度生长）的患者都存在体细胞PIK3CA突变。然而，在大约四分之一的患者中，没有检测到这种突变，这表明存在其他原因。与综合征病例（CLOVES和PROS）相比，我们在常见和合并LMs中更频繁地检测到热点突变。因此，诊断性基因分型不应局限于PIK3CA热点突变。此外，综合征中较高的突变等位基因频率表明其在患者组织中的分布更广，便于检测。临床试验已经证明西罗莫司和Alpelisib在治疗LM或PROS患者中的疗效。基因分型可能会提高疗效，因为治疗可能更有针对性，而且反应可能因pik3ca突变的存在和类型而异。在线版本包含补充资料，可在10.1186/s13023-021-01898-y获得。
Theragnostic management, treatment according to precise pathological molecular targets, requests to unravel patients’ genotypes. We used targeted next-generation sequencing (NGS) or digital droplet polymerase chain reaction (ddPCR) to screen for somatic PIK3CA mutations on DNA extracted from resected lesional tissue or lymphatic endothelial cells (LECs) isolated from lesions. Our cohort (n = 143) was composed of unrelated patients suffering from a common lymphatic malformation (LM), a combined lymphatic malformation [lymphatico-venous malformation (LVM), capillaro-lymphatic malformation (CLM), capillaro-lymphatico-venous malformation (CLVM)], or a syndrome [CLVM with hypertrophy (Klippel-Trenaunay-Weber syndrome, KTS), congenital lipomatous overgrowth-vascular malformations-epidermal nevi -syndrome (CLOVES), unclassified PIK3CA-related overgrowth syndrome (PROS) or unclassified vascular (lymphatic) anomaly syndrome (UVA)]. We identified a somatic PIK3CA mutation in resected lesions of 108 out of 143 patients (75.5%). The frequency of the variant allele ranged from 0.54 to 25.33% in tissues, and up to 47% in isolated endothelial cells. We detected a statistically significant difference in the distribution of mutations between patients with common and combined LM compared to the syndromes, but not with KTS. Moreover, the variant allele frequency was higher in the syndromes. Most patients with an common or combined lymphatic malformation with or without overgrowth harbour a somatic PIK3CA mutation. However, in about a quarter of patients, no such mutation was detected, suggesting the existence of (an)other cause(s). We detected a hotspot mutation more frequently in common and combined LMs compared to syndromic cases (CLOVES and PROS). Diagnostic genotyping should thus not be limited to PIK3CA hotspot mutations. Moreover, the higher mutant allele frequency in syndromes suggests a wider distribution in patients’ tissues, facilitating detection. Clinical trials have demonstrated efficacy of Sirolimus and Alpelisib in treating patients with an LM or PROS. Genotyping might lead to an increase in efficacy, as treatments could be more targeted, and responses could vary depending on presence and type of PIK3CA-mutation. The online version contains supplementary material available at 10.1186/s13023-021-01898-y.
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影响因子：
3.7
作者：
Loconte DC;Grossi V;Bozzao C;Forte G;Bagnulo R;Stella A;Lastella P;Cutrone M;Benedicenti F;Susca FC;Patruno M;Varvara D;Germani A;Chessa L;Laforgia N;Tenconi R;Simone C;Resta N
通讯作者：
Resta N
影响因子：
2
作者：
Keppler-Noreuil, Kim M.;Sapp, Julie C.;Lindhurst, Marjorie J.;Parker, Victoria E. R.;Blumhorst, Cathy;Darling, Thomas;Tosi, Laura L.;Huson, Susan M.;Whitehouse, Richard W.;Jakkula, Eveliina;Grant, Ian;Balasubramanian, Meena;Chandler, Kate E.;Fraser, Jamie L.;Gucev, Zoran;Crow, Yanick J.;Brennan, Leslie Manace;Clark, Robin;Sellars, Elizabeth A.;Pena, Loren D. M.;Krishnamurty, Vidya;Shuen, Andrew;Braverman, Nancy;Cunningham, Michael L.;Sutton, V. Reid;Tasic, Velibor;Graham, John M., Jr.;Geer, Joseph, Jr.;Henderson, Alex;Semple, Robert K.;Biesecker, Leslie G.
通讯作者：
Biesecker, Leslie G.
影响因子：
9.8
作者：
Limaye, Nisha;Kangas, Jaakko;Vikkula, Miikka
通讯作者：
Vikkula, Miikka
影响因子：
9.8
作者：
Kurek, Kyle C.;Luks, Valerie L.;Warman, Matthew L.
通讯作者：
Warman, Matthew L.
DOI：
10.1002/ajmg.c.31531
发表时间：
2016-12
期刊：
American journal of medical genetics. Part C, Seminars in medical genetics
影响因子：
--
作者：
Keppler-Noreuil KM;Parker VE;Darling TN;Martinez-Agosto JA
通讯作者：
Martinez-Agosto JA