Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic Characteristics

Khan, Maliha; Loree, Jonathan M.; Advani, Shailesh; Ning, Jing; Li, Wen; Pereira, Allan Andresson Lima; Lam, Michael; Raghav, Kanwal; Morris, Van K.; Broaddus, Russell R.; Maru, Dipen M.; Overman, Michael J.; Kopetz, Scott

doi:10.1016/j.clcc.2018.07.005

Cited by 37 publications

(38 citation statements)

References 56 publications

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“…GNAS mutation has been previously described in mucinous neoplasms of the pancreas and peritoneal carcinomatosis from appendiceal adenocarcinomas 35,36 . While the clinical significance of GNAS mutation in primary CRC is vaguely understood, a recent review by Khan et al, 37 demonstrated that GNAS mutation was more common in mucinous CRC adenocarcinoma. In that series, GNAS mutation was present in 6.9% of mucinous adenocarcinomas and was a poor prognostic factor on univariate analysis.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma

Stein

Williard

Xiu

et al. 2020

Journal of Surgical Oncology

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Background and Objectives: Peritoneal metastases (PM) from primary colorectal cancer (pCRC) are associated with poor outcomes; however, molecular differences are not well defined. Methods:We compared unpaired tumor profiles of patients with pCRC and PM from Caris Life Sciences. Testing included next-generation sequencing of 592 genes, microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were test-defined as pathogenic (PATH).Results: Six hundred seventeen pCRC and 348 PM patients had similar gender (55% male) and age (median 59). PATHs were similar between PM and pCRC in KRAS, BRAF, SMAD2, SMAD4, and PTEN. pCRC PATHs were increased in APC (76% vs 48%, P < .01), ARID1A (29% vs 12%, P < .05), TP53 (72% vs 53%, P < .01), PIK3CA (22% vs 15%, P < .05), and FBXW7 (13% vs 7%, P < .01) compared with PM. Mucinous PM had more PATHs in GNAS (19% vs 8%, P = .032) while nonmucinous PM had more PATHs in BRAF (13% vs 8%, P = .027). Right-sided PM had decreased PATHs in APC (39% vs 68%, P < .0001), ARID1A (7% vs 38%, P < .004), and TP53 (48% vs 65%, P = .033) while there were no difference for left-sided PM. Nine percent of pCRC and 6% of PM were MSI-high (P = NS). There was no difference in TMB-high, TMB-intermediate, or TMB-low between PM and pCRC.Conclusions: PM have similar rates of KRAS mutation with increased PATHs in GNAS (mucinous) and BRAF (nonmucinous) compared to pCRC. No differences in MSI or This study was presented in part at the

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Section: Discussionmentioning

confidence: 99%

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma

Stein

Williard

Xiu

et al. 2020

Journal of Surgical Oncology

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“…Mucinous colon/appendix cancers display phenotypic and genotypic characteristics that are predictive of responses to dual MEK‐PI3K inhibition. Mucinous colon cancers are more likely to occur in younger female patients; particularly the right colon; follow the serrated pathway for carcinogenesis; and are more likely to have RAS, RAF, and GNAS mutations . Similarly, mucinous appendix cancers are almost always KRAS mutant, and low‐grade histology almost uniformly demonstrates GNAS mutations .…”

Section: Discussionmentioning

confidence: 99%

Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors

et al. 2020

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Molecular‐targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK‐PI3K drug therapy against KRAS mutated mucin 2 (MUC2)‐secreting LS174T cells and patient‐derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co‐therapy. Co‐treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)‐induced synergistic cytotoxicity and intrinsic mitochondrial‐mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)‐associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock‐down assays demonstrated that mitochondrial‐mediated apoptosis in LS174T cells was not ERS‐dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post‐translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient‐derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK‐PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co‐treatment based on their unique phenotypic and genotypic characteristics.

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“…A retrospective study of 90 SMAD4 -mutated ACAs reported poorer survival rates in patients with SMAD4 -mutated tumors, but did not include mucinous morphology as a potential risk factor [3]. Similarly, Mizuno et al reported worse survival, but did not report tumor morphology of the SMAD4 -mutated cancers [6], while Khan et al reported association of mucinous morphology with SMAD4 mutation and worse prognosis [11]. Recognizing these knowledge gaps, our comprehensive study using a stringent retrospective case-control design confirms that SMAD4 mutations are associated with higher tumor stage, nodal metastasis, tumor deposits in adipose tissue, mucinous morphology, and RAS mutations.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we also investigated the relationship between SMAD4 and other gene mutations, especially RAS genes since these two are closely associated. KRAS mutations have been reported to correlate with mucinous differentiation in CRCs [11,18], yet the mucinous differentiation in SMAD4 m tumors is independent of KRAS mutation status. Tumors with RAS mutations are known to be intrinsically resistant to anti-EGFR therapy [19,20]; however, it has been shown that SMAD4 mutation is an independent factor of resistance to anti-EGFR therapy [3].…”

Section: Discussionmentioning

confidence: 99%

“…Missense mutations in the MH2 domain were the most common alterations. SMAD4 mutations have also been observed in cancers with mucinous differentiation, especially those of high grade [8–11]. We carried out a retrospective case-control study aimed at characterizing the distinctive clinicopathological features of SMAD4 -mutated intestinal adenocarcinomas (ACAs).…”

Section: Introductionmentioning

confidence: 99%

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Clinicopathological characterization of SMAD4-mutated intestinal adenocarcinomas: A case-control study

et al. 2019

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The SMAD4 tumor suppressor gene product inhibits transforming growth factor-β-mediated signaling and is mutated in ~10% of colorectal carcinomas. The prognostic significance of SMAD4 mutations has been controversial. We studied the pathological and clinical characteristics of SMAD4-mutated intestinal adenocarcinomas using a retrospective case-control study design. Cases and controls were identified among 443 primary adenocarcinomas that had undergone next generation DNA sequencing (NGS) with the Ion AmpliSeq Cancer Hotspot Panel v2, which evaluates 50 cancer-related genes. Twenty-eight SMAD4-mutated (SMAD4m) patients were matched 1:2 with 56 consecutive SMAD4 wild-type (SMAD4wt) control patients from the same analysis stream. Compared with the SMAD4wt controls, the SMAD4m tumors were of higher stage (P = 0.026) and were more likely to feature mucinous differentiation (P = 0.0000), to occur in the setting of Crohn’s disease (P = 0.0041), and to harbor concurrent RAS mutations (P = 0.0178). Tumor mucin content was significantly correlated with mutations involving the MH2 domain of the SMAD4 protein (P = 0.0338). Correspondence between mutation sites and morphology was demonstrated directly in a mixed adenocarcinoma and neuroendocrine tumor where SMAD4 mutations involving different protein domains were found in histologically disparate tumor regions despite both containing identical KRAS and TP53 mutations.

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Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic Characteristics

Abstract: Compared with nonmucinous adenocarcinoma, the mucinous histologic type is associated with a worse prognosis, even when controlling for known prognostic features. This unique biologic behavior should be considered in the treatment and prognostic assessment of patients with CRC.

Cited by 37 publications

References 56 publications

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma

Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors

Clinicopathological characterization of SMAD4-mutated intestinal adenocarcinomas: A case-control study

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