Abstract
Signet ring cell carcinoma (SRCC) is rare: about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however the underlying molecular characteristics are unknown. SRCCs were analyzed using NGS, immunohistochemistry, and in situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. A total of 8500 CRC and 1100 GC were screened. Seventy-six SRCC were identified from the CRC cohort (<1) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%); in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%). When compared to non-SRCC histology (N = 3522), CRC-SRCC (N = 37) more frequently had mutations in BRCA1 (11% vs 1%, P < 0.001) and less frequently mutations in APC (19% vs 78%, P < 0.001 KRAS (22% vs 51%, P = 0.001) and TP53 (47% vs 73%, P = 0.001). Among the GC cohort, SRCC (N = 54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, compared to non-SRCC (N = 540). Our data suggest that SRCCs harbor a similar molecular profile, regardless of the tumor location. Tailored therapy may become available for these patients.
INTRODUCTION
Signet-ring cell carcinoma (SRCC) is defined according to the World Health Organization (WHO) classification as a poorly cohesive carcinoma composed predominantly of tumor cells with prominent cytoplasmic mucin and a crescent-shaped nucleus eccentrically placed [1].
Besides gastric cancer, SRCC histology may be found in several other solid cancers, including colorectal cancer (CRC) [2], esophagus [3], breast [4], prostate [5], among others, although the prevalence of SRCC in these tumor types is very low [6]. However, the molecular characteristics underlying the biology of these tumors have not been elucidated yet.
Formally, a cancer is labeled a SRCC if greater than 50% of tumor cells show prominent intracytoplasmic mucin and an eccentrically placed crescent-shaped nucleus, whereas adenocarcinomas with less than 50% signet ring cells are classified as “adenocarcinomas” with a signet ring cell component [7, 8].
Regarding gastric cancer, despite a decrease in the overall incidence of gastric cancer in recent decades, the incidence of signet-ring cell carcinoma (SRCC) is constantly increasing globally, accounting for 35–45% of gastric adenocarcinoma cases in recent studies [9, 10]. Indeed, its incidence increased tenfold between 1970 and 2000 [11]. This increase in prevalence can be partially explained by changes in the pathological classifications used to characterize these cancers. It is important to understand that signet-ring cell adenocarcinomas are always classified, by definition, as “undifferentiated type” by Nakamura and as “diffuse type” by Lauren. But, conversely, not all gastric cancers classified as “undifferentiated” or “diffuse” are signetring cell cancers. Demographically, SRCC is more frequent in women and in younger patients than non-SRCC [12]. The prognosis of signet-ring cell adenocarcinoma is still debated and appears to depend on the stage of the cancer at the time of diagnosis [13]. In fact, in early gastric cancer, patients with SRCC demonstrated more favorable prognoses than those with adenocarcinomas, while SRCC patients with advanced gastric cancer had a worse prognosis [14]. Recently, Kong et al. [15] showed that SRCC histology was correlated with a poor prognosis in terms of recurrence in node-negative gastric cancer patients and that SRCC histologic analysis combined with AJCC staging may be an effective method for prediction of the recurrence rate.
Regarding CRC, many studies have reported a younger median age of onset for SRCC compared to CRC adenocarcinomas [16–19]. The incidence of colorectal cancer in younger patients is rising, posing a global health issue. The cause of this trend remains unknown, although lack of screening, obesity, physical inactivity, and Western diets may play a crucial role in early-onset CRC [20]. Due to the rarity of the histology, specific SRCC risk factors are not known. Since shared risk factors might exist, further investigations into causality are necessary to develop potential preventive strategies. Few studies clearly showed higher rates among women as is seen in gastric SRCC, while others have found no difference between men and women [21]. Inamura and colleagues [22] showed that even when the signet-ring cell component was less than 50% the finding was associated with higher mortality, independent of other clinicopathologic and molecular features (microsatellite instability - MSI, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF, and PIK3CA mutations) in CRC patients. In CRC, SRCC is generally considered to be associated with MSI-high and molecular features common to other MSI-high and mismatch repair deficient (dMMR) CRCs. Although MSI-high is a well-established prognostic biomarker for better survival in patients with localized disease stages, signet-ring cell carcinoma is associated with shorter survival in CRC patients [23]. More recently, a huge effort by authors from The University of Texas MD Anderson Cancer Center, demonstrated that SRCCs are more commonly found in patients with right-sided tumors, poorly differentiated tumors or peritoneal metastasis. SRCC were commonly found with KRAS wild-type (WT), APC WT and PIK3CA WT, while no significant association was observed between SRCC and MSI, NRAS, BRAF, SMAD4, TP53 or FBXW7 status. Finally, patients with SRCC tumors had significantly worse overall survival (OS) than patients with adenocarcinomas [16].
Therefore, further studies are warranted to elucidate molecular mechanisms accounting for the aggressive behavior.
To our knowledge, our research is one of the largest to comprehensively characterize the molecular features of SRCC, focusing on gastric cancers and CRCs. We investigate whether SRCCs harbor different molecular characteristics compared with non-SRCC counterparts. In addition, we compare SRCCs tumors arising from different locations (e.g., gastric SRCC vs CRC SRCC) to evaluate whether SRCC histology harbor molecular similarities, regardless of tumor location.
RESULTS
A total of 11,768 patients (10,459 with CRC and 1309 with GC) were included in this study and were screened for any SRCC histology. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%), of which 54 and 45 were profiled with 592-gene panels, respectively and the rest with the 44-gene panel (Fig. 1).
Fig. 1. Patient demographics.
Consort diagram.
The most frequently mutated genes among the CRC-SRCC are TP53 (47%), ARID1A (26%), APC (25%), KRAS (22%), RNF43 (16%), KMT2D (12%), KMT2C (11%), SMAD4 (10%), BRAF (10%) and BRCA1 (7%): for this analysis we combined both the 592-gene and 44-gene DNA data into a single cohort. Twenty percent of CRC-SRCC were NGS-MSI and 17% showed TMB-high (Fig. 2). From 592-gene cohort only, which was used for the comparison to the traditional CRC, when compared to non-SRCC histology (N = 3522), CRC-SRCC more frequently had mutations in BRCA1 (9.1% vs 1%, P = 0.002) and less mutations in APC (22% vs 78%, P < 0.001), KRAS (20% vs 51%, P = 0.001) and TP53 (48% vs 73%, P = 0.001) (Fig. 3).
Fig. 2.
Summary genomic findings of CRC-SRCC.
Fig. 3. Signet ring cell histology vs non-SRCC from colorectal primary sites.
When compared to non-SRCC histology (N= 3522), CRC-SRCC showed more frequently mutation in BRCA1 (9.1% vs 1%, P= 0.002) and less mutation in APC (22% vs 78%, P < 0.001), KRAS (20% vs 51%, P= 0.001) and TP53 (48% vs 73%, P= 0.001).
The most frequently mutated genes in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%), BAP1 (7%), PIK3CA (7%), ERBB2 (5%). PD-L1 overexpression was 45%, NGS-MSI was seen in 3.5% of GC-SRCC; only 1.8% showed TMB-high (Fig. 4).
Fig. 4.
Summary genomic findings of Gastric-SRCC.
Among the GC cohort, SRCC (N = 54) had a higher frequency of mutations in CDH1 (20% vs 8%, P = 0.005), BAP1 (7.4% vs 2%, P = 0.039), and ERBB2 (9.3% vs 3.9%, P = 0.072), and a higher rate of amplification in MYB (4.1% vs 0%, P = 0.005) compared to nonSRCC (N = 540), although none reached statistical significance after correction for multiple comparisons (Fig. 5).
Fig. 5. Signet ring cell histology vs non-SRCC from gastric primary sites.
Among GC cohort, SRCC had a higher frequency of mutations in CDH1 (20% vs 8%, P = 0.005), BAP1 (7.4% vs 2%, P = 0.039), and ERBB2 (9.3% vs 3.9%, P = 0.072), and higher rate of amplification MYB (4.1% vs 0%, P = 0.005) compared to nonSRCC (N = 540), although none reached statistical significance after multiple test correction.
When we compared GC-SRCC vs. CRC-SRCC, only the mutation rate in APC (0% vs 25%) and KRAS (2% vs 22%) genes were significantly different (P < 0.001). Furthermore, increased rates of MSI (20% vs 3.5%, P = 0.008) and high TMB (17.8 vs 1.8, P = 0.013) were seen in CRC-SRCC compared to GC-SRCC (Fig. 6).
Fig. 6. Comparison of signet ring cell carcinomas between gastric and colorectal primaries.
When we compared GC-SRCC vs. CRC-SRCC, only the mutation rate in APC (0% vs 25%) and KRAS (2% vs 22%) genes were significantly different (P < 0.0001). Increased rates of MSI (20% vs 3.5%, P = 0.008) and high TMB (17.8% vs 1.8%, P = 0.013) were seen in CRC-SRCC compared to GC-SRCC.
DISCUSSION
Signet ring cells are characterized by the presence of a large central optically clear droplet of cytoplasmic mucin that displaces the nucleus to the cell periphery [24].
The World Health Organization (WHO) classified SRCCs as a group of rare tumors defined by the content of signet ring celltype cells greater than 50%. However, there is a need for a better classification supported by conflicting data about the frequency and prognostic relevance of SRC histology [25]. Therefore, some authors suggested a different classification to standardize the definition of GC-SRCC: they proposed that only WHO “poorly cohesive” GC with more than 90% signet ring cell morphology should be classified as SRCC [26]. In CRC-SRCC other authors reported that even less than 50% of signet ring cell component is associated with a worse prognosis [12]. Due to the worse prognosis and the differences in response rate to the common therapeutic schedules, better classification of this rare histological subtype is needed.
It seems that colorectal cancers with SRC histology do not develop through the usual sequence of colorectal carcinogenesis, arising de novo without passing through the adenoma-carcinoma transformation [27]. The most frequent mutations involved in the adenoma-carcinoma tumorigenic progression are APC, KRAS, and PIK3CA [28]. A prospective targeted sequencing of 1134 CRCs identified in the subgroup of microsatellite stable (MSS) patients (N = 1027, only 5 patients with SRC histology) the most frequently mutated genes are as follows: 79% harbored APC mutation, 44% KRAS mutation, and 18% PIK3CA mutation [29]. According to the Tumor Cancer Genome Atlas, the rate of gene mutations in CRC was: APC 51% in hypermutated samples vs. 81% in non-hypermutated, KRAS 43%, and PIK3CA 18% in non-hypermutated patients [30]. Our analysis confirmed a lower rate of these mutations in CRC-SRCC (APC: 25% and KRAS: 22%).
To date, therapy recommended for patients with CRC-SRCC is identical to that recommended for adenocarcinomas. As SRCCs are frequently diagnosed in an advanced tumor stage, typically only palliative chemotherapy is recommended [31]. It was reported that CRC-SRCC, in all stages, is usually insensitive to irinotecan, oxaliplatin, and 5-fluorouracil [32]. Despite that, in a SEER population analysis (1675 patients) an improvement in survival was reported in 936 stage II-III patients treated with undefined (single agent or doublet) postoperative adjuvant chemotherapy [33]. The actual clinical benefit gain from adjuvant chemotherapy in early-stage CRC-SRCC remains unclear, as randomized studies in this rare subgroup are lacking. For advanced disease, systemic treatment remains the primary treatment option, however, SRCC seems to be less sensitive to commonly used chemotherapy drugs, possibly due to the lower proliferation activity of these cells [31, 32]. A comprehensive characterization of molecular features of CRC-SRCC may help to find new histology-specific tailored therapies.
A personalized approach has not been proposed for gastric cancer with signet ring cell histology. Mengardo et al. suggested that multimodal therapy may be the best option for these patients [34]. Supporting this, a SEER population analysis highlighted the effect of preoperative radiotherapy (RT) in improving survival for patients with GC-SRCC [35]. The chemosensitivity of GC-SRCC remains undefined, as conflicting data has been reported on the use of 5-fluorouracil, platinum derivates, and taxane-based chemotherapy in a perioperative setting [13]. Therefore, some authors suggested performing front-line surgery without neoadjuvant treatment when possible [36]. In the metastatic setting, the use of docetaxel, 5-fluorouracil, and oxaliplatin may give an acceptable response rate, at least similar in magnitude to that benefit in patients with non-SRCC histology [13].
NGS-based therapeutic approaches have yet to be fully explored, for both gastric and colon SRCC. Our analysis showed that 20% of CRC-SRCC were MSI-High, allowing for the consideration of pembrolizumab as first-line therapy, a new standard treatment in metastatic MSI-high CRC [37]. A similar approach may be useful in GC-SRCC (MSI-High was found in 3.5% of GC-SRCC). Results from the phase II Keynote-158 study demonstrated a clinical benefit of pembrolizumab, after first-line treatment, among MSI-high non-CRC solid tumors [38]. However, no robust data are available on the efficacy of Pembrolizumab in SRCC subpopulation of patients as well as on SRCC histology as positive or negative predictive biomarkers for immunotherapy in gastric and/or CRC cancer patients [39]. Thus, further research into biomarkers of SRCC immune microenvironment may highlight targets for immunotherapy [40].
Additionally, targeting mutated DNA damage repair genes in gastrointestinal tumors is still at an early stage of development, but could be a valid option in those SRCC who harbor a BRCA1 mutation [41]. Our study showed that 7% of CRC-SRCC harbored a BRCA1 mutation, making this a viable therapeutic target. Clinical trials are ongoing to investigate the potential role of Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) in both gastric [42] and CRC patients [43].
Furthermore, our analysis revealed that further targetable gene alterations were detectable in SRCCs: RNF43, PIK3CA, ERBB2 as well as BRAF. Further study to identify activation pathways and potential therapeutic targets are needed [16].
We acknowledge that there are some limitations to our study including the retrospective nature of the analysis, the lack of clinical treatment and outcomes data to correlate with mutational analysis, as well as the heterogeneity of the study population unselected for tumor stage and site of tumors (primary vs metastatic sites). In addition, some further limitations exist in this study as well. The small number of included samples due to the rarity of SRCC may have given our study insufficient statistical power to identify all significant associations and differences such as molecular differences between MSI-high and microsatellite stable (MSS) tumors within SRCC cohort. Finally, in our dataset not enough data about tumor location (right vs left CRC) were available to establish a correlation between SRCC and primary site location.
CONCLUSION
Our research is one of the largest to molecularly characterize features of SRCC from gastric and colorectal tumors. Our data suggest that SRCCs harbor similar molecular profiles, regardless of the primary site of tumor origin. On the other hand, significant differences were observed between SRCCs and non-SRCC both within GC and CRC. Further studies are warranted to elucidate molecular mechanisms accounting for the aggressive behavior of SRCCs, as well as to identify activation pathways and potential therapeutic targets.
METHODS
Tumors submitted to Caris Life Sciences (Phoenix, AZ) for routine molecular profiling between January 2013 and January 2018 were reviewed from a de-identified database. Cases were reviewed from the Caris database based on available pathological notation using the search terms “signet ring cell”. Identified cases were reviewed and designated as primary signet ring cell, mixed signet ring cell, or rare signet ring cell based on the histological description provided with each specimen. Cases with histologic descriptions other than signet ring carcinoma were denoted separately.
Immunohistochemistry (IHC)
IHC was performed on FFPE sections. Protein staining was scored for intensity (0 = no staining; 1 += weak staining; 2 += moderate staining; 3 += strong staining) and staining percentage (0–100%) by pathologists. PD-L1 testing was performed using the SP142 anti-PD-L1 clone (Ventana, Tucson, AZ) and staining was measured on tumor cells alone. (2+ and/or 5% were considered positive for staining).
Next-generation sequencing (NGS)
NGS was performed in a CAP/CLIA/ISO-certified commercial laboratory on genomic DNA isolated from FFPE tumor samples using the NextSeq platform (Illumina, Inc., San Diego, CA.). A custom-designed SureSelect XT assay was used to enrich 592 whole-gene targets or 44-gene oncogenic hot-spot targets (Agilent Technologies). All variants were detected with >99% confidence based on allele frequency and amplicon coverage, with an average sequencing depth of coverage of 750 and an analytic sensitivity of 5%. Prior to molecular testing, tumor enrichment was achieved by harvesting targeted tissue using manual microdissection techniques. Genetic variants identified were interpreted by board-certified molecular geneticists and categorized as “pathogenic,” “presumed pathogenic,” “variant of unknown significance,” “presumed benign,” or “benign,” according to the American College of Medical Genetics and Genomics (ACMG) standards. When assessing mutation frequencies of individual genes, “pathogenic,” and “presumed pathogenic” were counted as mutations, whereas “benign”, “presumed benign” variants, and “variants of unknown significance” were excluded.
Microsatellite instability (MSI)
MSI was examined by counting the number of microsatellite loci that were altered by somatic insertion or deletion for each sample. The threshold to determine MSI by NGS was determined to be 46 or more loci with insertions or deletions to generate a sensitivity of >95% and specificity of >99%.
Tumor mutational burden (TMB)
TMB was measured by counting all nonsynonymous missense mutations found per tumor that had not been described previously as germline alterations [592 genes and 1.4 megabases (MB) sequenced/tumor]. Potential germline mutations are excluded by comparing data against dbSNP 137 full and 1000 Genomes Phase 3. The threshold to define TMB-high (TMB-H) was greater than or equal to 17 mutations/MB and was established by comparing TMB with MSI by fragment analysis in colorectal cancer cases, based on reports of TMB having high concordance with MSI-H in colorectal cancer. Differences in mean TMB was assessed using Student’s t test.
Statistical analysis
Chi-square test was performed for comparative analysis using SPSS v23 (IBM SPSS Statistics), and a statistical significance was defined as p value < 0.05.
DATA AVAILABILITY
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
ACKNOWLEDGEMENTS
This work was partly supported by National Cancer Institute (grant number P30CA014089), Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong research project and Ming Hsieh research fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute of the National Institutes of Health.
Footnotes
COMPETING INTERESTS
KP and WMK are employed by Caris Life Sciences. JLM and AS are consultants for Caris Life Sciences. AFS and RMG received research and travel support from Caris Life Sciences. MES and H-JL received travel support from Caris Life Sciences. AP, FC, FB, MDB, RT, MN, WZ, and PAP declare that there are no competing interests.
ETHICS APPROVAL
All human subjects’ data were de-identified prior to analysis. Thus, this research was determined to be exempt from the requirement for informed consent per the Western Institutional Review Board (WIRB).
ADDITIONAL INFORMATION
Reprints and permission information is available at http://www.nature.com/reprints
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.