Strategies for chemoselective treatment of lung cancer targeting methylthioadenosine phosphorylase (MTAP) deficiency-from chemosensitivity test to translational research

以下是我们对未术前治疗的非小细胞肺癌切除的MTAP研究的结论。MTAP- moab和RT-PCR检测MTAP基因缺失分别在81例和73例中分别有36例（44.4%）和24例（32.9%）在IHC中检测到MTAP阴性表达。两种方法的符合率为63/70(90%)，相关性显著（p< 0.001）。在PCR阳性和免疫组化阴性的所有7个样本中，观察到MTAP启动子病变的超甲基化。免疫组化诊断MTAP缺乏的实体瘤如肺癌具有足够的特异性。MTAP与p53基因P16的IHC表达模式的一致性为71%(65例中有35例MTAP(+)/ P16(+)， 65例中有11例MTAP(-)/ P16(-))，具有显著相关性（p< 0.001），而MTAP与p53的IHC表达模式的一致性仅为45%，无相关性。在没有MTA的培养条件下，MTAP状态不影响MTX和L-ALA的化疗敏感性。嘌呤合成打捞途径无效状态)。虽然在培养基中添加MTA对MTAP（-）癌细胞MTX和L-ALA的化学敏感性没有影响，但与MTX和L-ALA一起检测时，MTAP（+）癌细胞的抑制率分别从60.5%降至42.3% （p< 0.05）和55.7%降至29.9% （p< 0.001）。

Following are our conclusion of MTAP study on resected non-small cell lung cancer without preoperative treatment.1. Diagnosis of MTAP deficiency in lung cancerNegative expression of MTAP on IHC using MTAP-MoAb and MTAP gene deletion on RT-PCR were found in 36 (44.4%) of 81 cases and in 24 (32.9%) of 73 cases. The rate concordance between two methods was 63/70 (90%) with significant correlation (p<.001). Hypermethylation in the MTAP promoter lesion was observed in all seven samples showing positive PCR and negative IHC results. IHC was specific enough to diagnose MTAP deficiency in solid tumor as lung cancer.2. Correlation of IHC between on MTAP and on P16 of P53Concordance of expression pattern on IHC was found in 71% between MTAP and p16 (MTAP(+)/p16(+) in 35 of 65 cases and MTAP(-)/p16(-) in 11 of 65) showing significant correlation (p<.001), but in only 45% between MTAP and p53 without any correlation.3. In vitro test for Selective chemotherapy by purine de novo synthesis targeting MTAP deficiency in lung cancerMTAP status did not affect the chemosensitivity of MTX nor L-ALA in the culture condition without MTA (ie. Ineffective status for salvage pathway of purine synthesis). Although ddition of MTA in culture medium had no effect on chemosensitivity of MTX nor L-ALA in MTAP (-) cancer cells, it decreased inhibition rate from 60.5% to 42.3% (p<.05) and from 55.7% to 29.9% (P<.001) in MTAP (+) cancer cells when it was tested with MTX and L-ALA, respectively.