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240) Initiation from any of the downstream alternative sites tested in both genes would lead to loss of protein function, but further clinical data is required to confirm if these variants are associated with a high cancer risk.

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PMID:24302565 DOI:10.1002/mc.22116

2015 Molecular carcinogenesis

* Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity.

- Variants that disrupt the translation initiation sequences in cancer predisposition genes are generally assumed to be deleterious. However, few studies have validated these assumptions with functional and clinical data. Two cancer syndrome gene variants likely to affect native translation initiation were identified by clinical genetic testing: MLH1:c.1A>G p.(Met1?) and BRCA2:c.67+3A>G. In vitro GFP-reporter assays were conducted to assess the consequences of translation initiation disruption on alternative downstream initiation codon usage. Analysis of MLH1:c.1A>G p.(Met1?) showed that translation was mostly initiated at an in-frame position 103 nucleotides downstream, but also at two ATG sequences downstream. The protein product encoded by the in-frame transcript initiating from position c.103 showed loss of in vitro mismatch repair activity comparable to known pathogenic mutations. BRCA2:c.67+3A>G was shown by mRNA analysis to result in an aberrantly spliced transcript deleting exon 2 and the consensus ATG site. In the absence of exon 2, translation initiated mostly at an out-of-frame ATG 323 nucleotides downstream, and to a lesser extent at an in-frame ATG 370 nucleotides downstream. Initiation from any of the downstream alternative sites tested in both genes would lead to loss of protein function, but further clinical data is required to confirm if these variants are associated with a high cancer risk. Importantly, our results highlight the need for caution in interpreting the functional and clinical consequences of variation that leads to disruption of the initiation codon, since translation may not necessarily occur from the first downstream alternative start site, or from a single alternative start site.

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(1)65 null	(14)6 therapy	(27)3 of	(40)2 epigenetics
(2)48 cells	(15)6 tissues	(28)3 patients,	(41)2 growth
(3)33 and	(16)5 cells,	(29)3 research	(42)2 initiation
(4)32 cell	(17)5 progression	(30)3 was	(43)2 prevention
(5)23 patients	(18)5 registries	(31)2 (GC)	(44)2 registry
(6)15 in	(19)4 at	(32)2 biology	(45)2 study
(7)14 is	(20)4 deaths	(33)2 but	(46)2 susceptibility
(8)12 risk	(21)4 has	(34)2 can	(47)2 than
(9)12 screening	(22)4 mortality	(35)2 care	(48)2 treated
(10)12 stem	(23)3 (CRC)	(36)2 development	(49)2 treatment
(11)9 survivors	(24)3 as	(37)2 diagnostic	(50)2 using
(12)7 with	(25)3 cases	(38)2 drug
(13)6 are	(26)3 metabolism	(39)2 drugs

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--- WordNet output for cancer --- =>【病名】がん, 悪性腫瘍(しゅよう), がん腫, 社会悪, 癌 Overview of noun cancer The noun cancer has 5 senses (first 1 from tagged texts) 1. (15) cancer, malignant neoplastic disease -- (any malignant growth or tumor caused by abnormal and uncontrolled cell division; it may spread to other parts of the body through the lymphatic system or the blood stream) 2. Cancer, Crab -- ((astrology) a person who is born while the sun is in Cancer) 3. Cancer -- (a small zodiacal constellation in the northern hemisphere; between Leo and Gemini) 4. Cancer, Cancer the Crab, Crab -- (the fourth sign of the zodiac; the sun is in this sign from about June 21 to July 22) 5. Cancer, genus Cancer -- (type genus of the family Cancridae) --- WordNet end ---