Comprehensive analysis of mutational and clinicopathologic characteristics of poorly differentiated colorectal neuroendocrine carcinomas

Abstract

Poorly differentiated neuroendocrine carcinoma (NEC) is a rare subtype of colorectal cancer (CRC). This study aimed to investigate clinicopathologic characteristics of colorectal NECs and elucidate genomic differences and similarities between colorectal NECs and colorectal adenocarcinomas (ACs). A total of 30 colorectal NECs were screened for frequently identified CRC oncogenic driver genes by targeted next-generation sequencing of 382 genes. The median age of the patients was 67 years (range, 44 to 88 years). NECs occurred predominantly in the rectum (47%) and exhibited multiple adverse prognostic pathologic factors, including frequent lymphatic and vascular invasions, high rates of lymph node metastasis and distant metastasis and advanced TNM stage. The 1-, 3-, and 5-year overall survival rates of NEC patients were 46.7%, 36.4%, and 32.7%, respectively, with a median overall survival period of 11.5 months. In a molecular analysis, NECs showed high rates of BRAF mutation (23%), predominantly p.V600E (71%), and alterations in RB1 (47%), particularly deletion (57%). The frequencies and distributions of other genes, such as KRAS, APC, SMAD4, and PIK3CA, and microsatellite instability status were similar to those of ACs. These findings provide beneficial information for selecting therapeutic options, including targeted therapy, and a better understanding of the histogenesis of this tumour.

The genetic alterations of rectal neuroendocrine tumor and indications for therapy and prognosis: a systematic review

“…Similarly, the mutation frequency of APC was 36.7%, 53% and 71%, respectively, with the mean at 53.6%, and all three studies focused on NEC [22,26,27]. These studies also reported the KRAS mutation frequency of 25%, 36%, and 53.3%, respectively [22,26,27], with a mean of 38.1%. RB1 mutation has been identified in NET, and it was reported to be co-mutated with TP53 in small cell lung cancer, which is regarded as a cancer with neuroendocrine cell origin [28].…”

“…It exhibited a huge fluctuation, which may be caused by different ratios of samples with distinct pathological grades. For example, the studies reporting 10.1% and 14.3% mutational frequency focused on G1 and G2 NETs [19,25], while the studies reporting 43%, 57%, and 61% often focused on NEC [22,26,27]. Similarly, the mutation frequency of APC was 36.7%, 53% and 71%, respectively, with the mean at 53.6%, and all three studies focused on NEC [22,26,27].…”

“…Table 1 shows that BRAF mutations were reported in 9 out of 11 studies. Predominantly V600E, followed by D594G, and other rare sites have been implicated in rectal NETs [17][18][19][20][21][22][23][24][25][26][27]. Although the sample size of these studies varied, the frequency of BRAF mutations exhibited high consistency, ranging from 7.1% to 33.3%, with a median of 9% and a mean of 14.7%, Table 2 [17-19, 21-24, 26, 27].…”

“…Table 1 shows several studies examining the mutational landscape of rectal NET. It can be seen that in 6 studies reporting mutational landscape, the top mutated driver genes included TP53 in 5 studies, APC in 3 studies, KRAS in 3 studies, RB1 in 2 studies, CDKN2A in 2 studies, and PTEN in 2 studies [19,20,22,[25][26][27]. The mutational frequency of these main driver genes and the mean values have been summarized in Table 2.…”

“…For example, the studies reporting 10.1% and 14.3% mutational frequency focused on G1 and G2 NETs [19,25], while the studies reporting 43%, 57%, and 61% often focused on NEC [22,26,27]. Similarly, the mutation frequency of APC was 36.7%, 53% and 71%, respectively, with the mean at 53.6%, and all three studies focused on NEC [22,26,27]. These studies also reported the KRAS mutation frequency of 25%, 36%, and 53.3%, respectively [22,26,27], with a mean of 38.1%.…”