Pietrantonio Filippo, Yaeger Rona, Schrock Alexa B, Randon Giovanni, Romero-Cordoba Sandra, Rossini Daniele, Fucà Giovanni, Ross Jeffrey S, Kotani Daisuke, Madison Russell, Kim Seung Tae, Salvatore Lisa, Raimondi Alessandra, Pagani Filippo, Borelli Beatrice, Perrone Federica, Di Bartolomeo Maria, Miller Vincent A, Ali Siraj M, Lee Jeeyun, Yoshino Takayuki, de Braud Filippo, Falcone Alfredo, Hechtman Jaclyn F, Cremolini Chiara
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Università degli Studi di Milano, Milan, Italy.
JCO Precis Oncol. 2019 Dec;3:1-11. doi: 10.1200/PO.19.00136.
To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical (At-) mutations at codons other than 12, 13, 59, 61, 117, and 146.
By exploiting five next-generation sequencing sources (Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study, and the Foundation Medicine database), we retrieved 175 At- mutated cases. Molecular data were obtained from 163 samples from Memorial Sloan Kettering Cancer Center and the Foundation Medicine database. Clinical data were available for 27 At--positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study.
At- mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable microsatellite instability status, 11 (8%) were microsatellite instability high. POLE exonuclease domain mutations had higher frequency (7%) than expected and were found only in microsatellite-stable tumors with high tumor mutational burden (TMB). Overall, 17% (28 of 163) of At- cases had TMB greater than 20 mutations/Mb. Co-occurring typical /BRAF V600E mutations and mutations, presumed to cause RAS activation, were found in 30% and 12% of samples, respectively (up to 43% and 50%, respectively, in TMB-high samples). Patients with wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At-, typical , or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively ( < .001). No significant OS difference ( = .240) was found between patients with At- versus typical -mutated mCRC. Only one of six patients evaluable for primary resistance to anti-epidermal growth factor receptors achieved tumor response.
At- mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations.
描述在第12、13、59、61、117和146密码子以外发生罕见非典型（At-）突变的转移性结直肠癌（mCRC）的临床和分子特征。
通过利用五个二代测序来源（意大利合作项目、纪念斯隆凯特琳癌症中心、三星医疗中心、综合癌症基因组学抗表皮生长因子受体单克隆抗体生物标志物研究（BREAC）以及Foundation Medicine数据库），我们检索到175例At-突变病例。分子数据来自纪念斯隆凯特琳癌症中心和Foundation Medicine数据库的163个样本。临床数据来自意大利合作项目、纪念斯隆凯特琳癌症中心、三星医疗中心和BREAC研究的27例At-阳性和467例阴性病例。
在18270例mCRC中，163例（0.9%）检测到At-突变。在133例可评估微卫星不稳定性状态的病例中，11例（8%）为微卫星高度不稳定。POLE核酸外切酶结构域突变的频率（7%）高于预期，且仅在具有高肿瘤突变负荷（TMB）的微卫星稳定肿瘤中发现。总体而言，17%（163例中的28例）的At-病例TMB大于20个突变/Mb。分别在30%和12%的样本中发现了同时存在的典型/KRAS V600E突变和推测导致RAS激活的NRAS突变（在TMB高的样本中分别高达43%和50%）。KRAS野生型mCRC患者的中位总生存期（OS）为42.1个月，而携带孤立At-、典型KRAS或BRAF V600E突变的患者中位OS分别为32.3、30.0和17.9个月（P<0.001）。At-突变与典型KRAS突变的mCRC患者之间未发现显著的OS差异（P=0.240）。在6例可评估抗表皮生长因子受体原发性耐药性的患者中，只有1例出现肿瘤反应。
At-突变可能是RAS通路激活的标志物，并且可能与POLE核酸外切酶结构域突变的高共现率相关。
