Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms.
Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms.
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DOI：
10.3390/cancers13133246
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发表时间：
2021-06-29
期刊：
影响因子：
5.2
通讯作者：
Moliterno AR
中科院分区：
文献类型：
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作者：
Braunstein EM;Chen H;Juarez F;Yang F;Tao L;Makhlin I;Williams DM;Chaturvedi S;Pallavajjala A;Karantanos T;Martin R;Wohler E;Sobreira N;Gocke CD;Moliterno AR
骨髓增生性肿瘤(MPN)的家族聚集性是众所周知的，在MPN患者的一级亲属中，MPN的风险增加了5-7倍。然而，这种疾病的遗传易感性仍然知之甚少。对一个家族性MPN家系进行外显子组测序，然后进行病例对照分析，确定了HER2/ERBB2基因中与MPN表型相关的胚系变异。ERBB2/HER2是一个新的易感基因，与其他风险等位基因一起导致癌症风险。骨髓增生性肿瘤(MPN)的家族性病例相对常见，但很少有遗传危险因素被发现。对一个患有MPN和黑色素瘤的家族性癌症综合征家族的外显子组测序产生了ERBB2/HER2基因的胚系变体，该基因与疾病共分离。为了进一步探讨胚系ERBB2变异是否与MPN易感性有关，我们分析了1604例血液系统恶性肿瘤患者中ERBB2变异的频率，其中包括236例MPN。MPN患者中罕见的胚系ERBB2编码变异的频率高于非MPN血液系统恶性肿瘤(8.9%vs.4.1%，OR2.4，95%CI：1.4~4.0，p=0.0028)和作为内对照的非MPN患者(8.9%vs.2.7%，OR3.5，95%CI：1.4~8.3，p=0.0053)。这一发现通过与1587例未选择血液系统恶性肿瘤的独立对照队列的比较而得到证实(MPN组8.9%，对照组5.2%，p=0.040)。已发现的最常见的变异体ERBB2 c.1960A>；G；p.I654V在MPN病例中的出现频率是预期频率的两倍以上。这些数据表明，ERBB2中罕见的生殖系编码变异与MPN发生的风险增加有关。ERBB2基因是一个新的易感基因，它可能与额外的风险等位基因一起导致癌症风险。
Familial clustering of myeloproliferative neoplasms (MPN) is well known, with a 5- to 7-fold increased risk of MPN among first-degree relatives of MPN patients. However, the genetic susceptibility of this disease remains poorly understood. Exome sequencing of a familial MPN pedigree followed by a case-control analysis identified germline variants in the HER2/ERBB2 gene that associate with the MPN phenotype. ERBB2/HER2 is a novel susceptibility locus which contributes to cancer risk in combination with additional risk alleles. Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates with disease. To further investigate whether germline ERBB2 variants contribute to MPN predisposition, the frequency of ERBB2 variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline ERBB2 coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, p = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, p = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, p = 0.040). The most frequent variant identified, ERBB2 c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in ERBB2 are associated with an increased risk for development of MPN. The ERBB2 gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles.
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影响因子：
64.8
作者：
Bick AG;Weinstock JS;Nandakumar SK;Fulco CP;Bao EL;Zekavat SM;Szeto MD;Liao X;Leventhal MJ;Nasser J;Chang K;Laurie C;Burugula BB;Gibson CJ;Lin AE;Taub MA;Aguet F;Ardlie K;Mitchell BD;Barnes KC;Moscati A;Fornage M;Redline S;Psaty BM;Silverman EK;Weiss ST;Palmer ND;Vasan RS;Burchard EG;Kardia SLR;He J;Kaplan RC;Smith NL;Arnett DK;Schwartz DA;Correa A;de Andrade M;Guo X;Konkle BA;Custer B;Peralta JM;Gui H;Meyers DA;McGarvey ST;Chen IY;Shoemaker MB;Peyser PA;Broome JG;Gogarten SM;Wang FF;Wong Q;Montasser ME;Daya M;Kenny EE;North KE;Launer LJ;Cade BE;Bis JC;Cho MH;Lasky-Su J;Bowden DW;Cupples LA;Mak ACY;Becker LC;Smith JA;Kelly TN;Aslibekyan S;Heckbert SR;Tiwari HK;Yang IV;Heit JA;Lubitz SA;Johnsen JM;Curran JE;Wenzel SE;Weeks DE;Rao DC;Darbar D;Moon JY;Tracy RP;Buth EJ;Rafaels N;Loos RJF;Durda P;Liu Y;Hou L;Lee J;Kachroo P;Freedman BI;Levy D;Bielak LF;Hixson JE;Floyd JS;Whitsel EA;Ellinor PT;Irvin MR;Fingerlin TE;Raffield LM;Armasu SM;Wheeler MM;Sabino EC;Blangero J;Williams LK;Levy BD;Sheu WH;Roden DM;Boerwinkle E;Manson JE;Mathias RA;Desai P;Taylor KD;Johnson AD;NHLBI Trans-Omics for Precision Medicine Consortium;Auer PL;Kooperberg C;Laurie CC;Blackwell TW;Smith AV;Zhao H;Lange E;Lange L;Rich SS;Rotter JI;Wilson JG;Scheet P;Kitzman JO;Lander ES;Engreitz JM;Ebert BL;Reiner AP;Jaiswal S;Abecasis G;Sankaran VG;Kathiresan S;Natarajan P
通讯作者：
Natarajan P
实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
影响因子：
20.3
作者：
Hinds, David A.;Barnholt, Kimberly E.;Gotlib, Jason
通讯作者：
Gotlib, Jason
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
30.8
作者：
通讯作者：
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