Montori Andrea, Germani Aldo, Ferri Mario, Milano Annalisa, Ranalli Teresa Valentina, Piane Maria, Pilozzi Emanuela
Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
Unit of Pathologic Morphological and Molecular Anatomy, Sant'Andrea University Hospital, Via di Grottarossa 1035, 00189 Rome, Italy.
Biomedicines. 2022 Dec 13;10(12):3247. doi: 10.3390/biomedicines10123247.
Neoadjuvant chemo-radiotherapy (nCRT) represents the standard of care for locally advanced rectal cancer (LARC); however, there exists no biomarker that can predict the cancer's response to treatment as less than 20% of patients experience pathological complete response (pCR). Ionizing radiations induce double strand breaks (DSBs) and trigger a DNA damage response (DDR) involving ATM, ATR, and the MRN complex (MRE11, Rad50, and NBS1). In this study, we performed an extensive mutational analysis of the genes involved in the DDR pathway in LARC patients who have undergone nCRT.
13 LARC patients with pCR and 11 LARC patients with partial response (pPR) were investigated using a NGS dedicated panel, designed for formalin-fixed paraffin-embedded (FFPE) samples, containing , , and genes. The identified variants were classified according to guidelines' recommendations.
Eight non-benign variants, six of which were observed in 3 (23%) out of 13 pCR patients, were identified. In particular, a pCR patient carried out a pathogenetic frameshift mutation in exon 21 of the gene. The two remaining non-benign missense variants were found in 2 (18%) out of 11 patients in the pPR group.
Our data show that the genes involved in the Homologous Recombination (HR) pathway are rarely mutated in LARC; however, given the identification of a missense mutation in RAD 50 in one case of pCR, it could be worth exploring its potential role as a biomarker in larger series.
新辅助放化疗（nCRT）是局部晚期直肠癌（LARC）的标准治疗方法；然而，由于只有不到20%的患者出现病理完全缓解（pCR），目前尚无能够预测癌症对治疗反应的生物标志物。电离辐射会导致双链断裂（DSB），并引发涉及ATM、ATR和MRN复合物（MRE11、Rad50和NBS1）的DNA损伤反应（DDR）。在本研究中，我们对接受nCRT的LARC患者DDR通路相关基因进行了广泛的突变分析。
使用专为福尔马林固定石蜡包埋（FFPE）样本设计的NGS专用面板，对13例pCR的LARC患者和11例部分缓解（pPR）的LARC患者进行了研究，该面板包含 、 和 基因。根据指南建议对鉴定出的变异进行分类。
共鉴定出8个非良性变异，其中6个在13例pCR患者中的3例（23%）中观察到。特别是，1例pCR患者在 基因的第21外显子发生了致病性移码突变。其余两个非良性错义变异在pPR组的11例患者中的2例（18%）中发现。
我们的数据表明，参与同源重组（HR）通路的基因在LARC中很少发生突变；然而，鉴于在1例pCR患者中鉴定出RAD 50的错义突变，在更大规模的研究中探索其作为生物标志物的潜在作用可能是值得的。
