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. 2020 Jun;121(8):1320-1328.
doi: 10.1002/jso.25899. Epub 2020 Mar 12.

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

Matthew K Stein  1 , Forrest W Williard  2 , Joanne Xiu  3 , Miriam W Tsao  4 , Michael G Martin  5 , Benjamin W Deschner  4 , Paxton V Dickson  4 , Evan S Glazer  4 , Danny Yakoub  4 , David Shibata  4 , Axel F Grothey  5 , Philip A Philip  6 , Jimmy J Hwang  7 , Anthony F Shields  6 , John L Marshall  8 , W Michael Korn  3 , Heinz-Josef Lenz  9 , Jeremiah L Deneve  4
Affiliations

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

Matthew K Stein et al. J Surg Oncol. 2020 Jun.

Abstract

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 TMB were identified between PM and pCRC tumors. These findings inform future study into the molecular profile of PM.

Keywords: BRAF; GNAS; KRAS; carcinomatosis; colon; molecular profile.

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Conflict of interest statement

CONFLICT OF INTERESTS

Dr Xiu and Dr Korn are employed by Caris Life Sciences. Dr Marshall is a consultant for Caris Life Sciences. The other authors declare that there are no conflict of interests. The content is solely the responsibility of the authors.

Figures

FIGURE 1
FIGURE 1
Comparison of pathogenic gene mutation rates between primary CRC (pCRC) and peritoneal metastases of all samples (A), right colon origin (B), left colon origin (C), and rectum origin (D). * significant values (P < .05). pCRC, primary colorectal cancer
FIGURE 2
FIGURE 2
Comparison of mucinous pathogenic gene mutation rates between pCRC and PM of mucinous (A) and nonmucinous (B) origin. * significant values (P < .05). pCRC, primary colorectal cancer; PM, peritoneal metastases
FIGURE 3
FIGURE 3
Comparison of tumor mutation burden (TMB) between primary CRC (pCRC) and peritoneal metastases. TMB low (TMB‐L) was defined as ≤6 mutations/megabase (MMb), TMB‐intermediate (TMB‐I) as 7 to 16 MMb and TMB‐high (TMB‐H) as ≥17 MMb. There was no significant difference in TMB between pCRC and PM. pCRC, primary colorectal cancer; PM, peritoneal metastases
FIGURE 4
FIGURE 4
Comparison of microsatellite instability (MSI) rates between primary CRC (pCRC) and peritoneal metastases between all tumors and based on tumor sidedness. There was no significant difference in MSI-high status between pCRC and PM. pCRC, primary colorectal cancer; PM, peritoneal metastases
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