Comment on ‘Wild-type APC prediction of poor prognosis in microsatellite-stable proximal colorectal cancer differs according to the age of onset'

José Perea; María Arriba; Daniel Rueda; Ricardo Sánchez; Juan Luis García; Jessica Pérez; Yolanda Rodríguez; Rogelio González-Sarmiento; Miguel Urioste

摘要

Sir, We read with interest the article by Jorissen et al (2015) , highlighting as conclusion that APC -wild-type (wt) status should be a marker of poor prognosis in microsatellite-stable (MSS) proximal colorectal cancer (CRC). Another important aspect underlined was that proximal APC -wt/MSS tumours exhibit features of the sessile serrated pathway, after testing that the prognostic value of the classification according to the APC status, and CRC location was reflected at the pathological and molecular level ( Jorissen et al , 2015 ). They analysed 746 patients, and the median ‘age of onset' of 70 years. Since a few years ago, we are trying to characterise an important subgroup within CRC, as it is early-onset CRC (EOCRC). To date, this subset of CRC appears to be different in comparison with others CRCs with older age of onset, especially those cases showing MSS ( Boardman et al , 2013 ; Kirzin et al , 2014 ; Perea et al , 2014 ). We have shown this item, studying EOCRC from clinico-pathological, familial, and molecular points of view, and compared all the features found with a subset of late-onset CRC (LOCRC; diagnosed at an age of 70 years or older; Perea et al , 2014 ; Arriba et al , 2015 ). Taking as the starting point the work by Jorissen et al (2015) , we have analysed the same aspects, but applying an age of onset criterion, and compared a total of 56 cases of EOCRC with other 87 LOCRC cases. The methods used to analyze the microsatellite instability status, CpG islands methylator phenotype (CIMP), chromosomal instability by array comparative genomic hybridisation, as well as the clinico-pathological variables described, have been published before ( Perea et al , 2014 ; Arriba et al , 2015 ). APC mutation status, as well as the other genes described by Jorissen et al (2015) , have been analysed by next-generation sequencing. First, the findings shown by Jorissen et al (2015) according to the prognostic results are confirmed only for LOCRC. In this particular age of onset, among patients with MSS tumours, APC -wt proximal cancers showed significantly inferior prognosis for overall survival (OS) and recurrence-free survival (RFS): 30 and 18 months, respectively, for proximal APC -wt/MSS tumours compared with proximal APC -mutated (mt)/MSS tumours (OS: 56; RFS: 50), and distal-MSS tumours (both ～40 and 30 months, respectively). Even though, EOCRC subset showed interestingly different results. Worst prognosis subgroup in this age of onset was distal APC -mt MSS CRCs, with 55 months of OS and 40 months of RFS. In the progression in relation to a better prognosis, the other distal-MSS CRC group ( APC -wt) appeared second, being those with the best prognosis, proximal APC-mt MSS cases (OS: 112; RFS: 96). Jorissen et al (2015) tested as well that the prognostic value of the classification according to the APC status and CRC location was reflected at the pathological and molecular level: first, the poor prognosis APC -wt/MSS cancers of the proximal colon consistently showed associations with features of the sessile serrated pathway, including poor differentiation, CIMP-high and BRAF mutation, and to a lesser extent mucinous histology and female gender. APC -mt/MSS distal cancers displayed the expected classic adenoma–carcinoma pathway features such as TP53 mutation and high IC, whereas APC -mt/MSS proximal cancers showed association with KRAS mutation and to a lesser extent with PIK3CA mutation, hallmarks of the alternate pathway. APC -wt/MSS distal cancers showed no consistently outstanding characteristics, although some tendency towards features of the sessile serrated pathway was noted. Although some of the subsets according to the APC mutation status and colon location are not too large in our series (proximal colon subsets), some conclusions should be given according to the differential clinico-pathological and molecular features showed by the APC status and colon location classification, when we compared them within the different age-of-onset subgroups. In relation to the EOCRC subgroup, the majority of the characteristics are equivalent for both proximal groups and the APC -mt/MSS distal cancers; only APC -wt/MSS distal cancers differed, being an important group of sporadic cases without showing any predominant feature of all studied cases. On the other hand, LOCRC fulfilled mostly all the features described by Jorissen et al (2015) , except with regard to the PIK3CA -mutation status. These results not only continue suggesting the different behaviour, in this case in relation to the prognosis, of the MSS-EOCRC cases but also define more accurately one of the groups within the EOCRC whose molecular basis remains unknown, and therefore, for whom a greater effort in its search is necessary: APC -wt/MSS distal EOCRC.

机译：主席先生，我们感兴趣地阅读了Jorissen等人（2015年）的文章，着重强调了APC野生型（wt）状态应该是微卫星稳定（MSS）近端大肠癌（CRC）预后不良的标志。强调的另一个重要方面是近端APC -wt / MSS肿瘤表现出无柄锯齿状路径的特征，在测试根据APC状态分类的预后价值和CRC位置反映在病理和分子水平后（Jorissen等等人，2015年）。他们分析了746名患者，中位“发病年龄”为70岁。自几年前以来，我们一直在尝试在CRC中表征一个重要的亚组，因为它是早发性CRC（EOCRC）。迄今为止，这一CRC子集似乎与其他发病年龄较大的CRC有所不同，尤其是那些表现出MSS的病例（Boardman等，2013; Kirzin等，2014; Perea等，2014）。我们已经显示了该项目，从临床病理，家族和分子的角度研究了EOCRC，并将发现的所有特征与一部分迟发性CRC（LOCRC;诊断为70岁或以上; Perea等等，2014; Arriba等，2015）。以Jorissen等人（2015）的工作为出发点，我们对相同方面进行了分析，但应用了发病年龄标准，并将总共56例EOCRC与其他87例LOCRC进行了比较。以前已经发表了用于通过阵列比较基因组杂交分析微卫星不稳定性状态，CpG岛甲基化子表型（CIMP），染色体不稳定性以及所述的临床病理变量的方法（Perea等，2014; Arriba等，2015年）。已通过下一代测序分析了APC突变状态以及Jorissen等人（2015）描述的其他基因。首先，Jorissen等人（2015年）根据预后结果显示的发现仅针对LOCRC得以证实。在这个特定的发病年龄中，MSS肿瘤患者中，APC -wt近端癌的总体生存期（OS）和无复发生存期（RFS）的预后明显较差：近端APC -wt /分别为30和18个月MSS肿瘤与近端APC突变（mt）/ MSS肿瘤（OS：56; RFS：50）和远端MSS肿瘤（分别为〜40和30个月）相比。即使EOCRC子集显示出有趣的不同结果。在该发病年龄中，最差的预后亚组是远端APC -mt MSS CRC，其OS为55个月，RFS为40个月。在与更好预后相关的进展中，另一个远端MSS CRC组（APC -wt）出现在第二位，即那些预后最好的近端APC-mt MSS病例（OS：112; RFS：96）。 Jorissen等人（2015）还测试了根据APC状态和CRC位置进行分类的预后价值反映在病理和分子水平上：首先，近端结肠APC -wt / MSS癌症预后较差与无柄锯齿状途径的特征相关，包括分化差，CIMP高和BRAF突变，以及粘液组织学和女性性别程度较低。 APC -mt / MSS远端癌表现出预期的经典腺瘤-癌途径特征，例如TP53突变和高IC，而APC -mt / MSS远端癌表现出与KRAS突变相关，在较小程度上与PIK3CA突变相关。途径。 APC -wt / MSS远端癌未显示出始终如一的突出特征，尽管已注意到无柄锯齿状途径特征的一些趋势。尽管在我们的系列中，根据APC突变状态和结肠位置的一些子集并不太大（结肠近端子集），但应根据APC状态和结肠位置所显示的不同的临床病理和分子特征给出一些结论分类，当我们在不同的发病年龄亚组中比较它们时。对于EOCRC亚组，近端组和APC-mt / MSS远端癌的大多数特征均相同。仅APC -wt / MSS远端癌有所不同，是一类重要的散发病例，未显示所有研究病例的任何主要特征。另一方面，除PIK3CA突变状态外，LOCRC几乎满足了Jorissen等人（2015）所述的所有功能。这些结果不仅继续暗示了MSS-EOCRC病例在这种情况下与预后相关的不同行为，而且更准确地定义了EOCRC中分子基础仍然未知的一组，因此，对于他们而言，寻找它的努力是必要的：APC -wt / MSS远端EOCRC。

Comment on ‘Wild-type APC prediction of poor prognosis in microsatellite-stable proximal colorectal cancer differs according to the age of onset'

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