Colorectal SRCC has been considered a distinct histological subtype of CRC based on clinicopathological features, genetic features and clinical outcomes. However, there are still some problems. First of all, SRCC is a rare subtype of colorectal cancer, but previous SRCC studies are focused only few cancer gene mutations and expressions or case reports. Some population-based studies have noted that SRCC commonly presents at a young age17. However, it remains controversial, as Lanjuan Li et al. reported a much older age at diagnosis, of 64.5 years old18. None of the above studies analyzed the differences in the distribution of different ABO blood groups, and our study revealed for the first time that blood group A was highly prevalent in younger people, while the other three blood groups were significantly more prevalent in older groups. A prospective study of a cohort of middle-aged or older Chinese men demonstrated a lower risk of all cancer for blood group B, as well as lower risk for gastrointestinal cancers including colorectal cancer19. However, the study did not analyze the relationship between different CRC subtypes and blood groups. Our study found that SRCC patients with blood group B were often diagnosed at an advanced stage, had rapid disease progression and a far worse PFS than people with blood group O. In addition, due to abnormal metabolism, PaCO2 levels were generally low in patients with blood group B, and the degree of anemia was more severe in patients with blood group B than other groups.
Secondly, the ABO blood group antigens could influence tumorigenesis by changing intercellular adhesion, membrane signaling and immune surveillance20. Some studies have reported the lack of association between ABO blood groups and CRC, Khalili et al found no significant association between blood group B and the overall risk of colon cancer21. However, Urun et al reported that ABO/Rh blood groups were significantly associated with CRC, and there was no relationship between KRAS mutation and ABO blood groups22. None of the previous studies analyzed the relationship between different subtypes of CRC and ABO blood groups. Since the clinicopathological features and genomic changes of different subtypes of CRC are completely different, previous studies on the relationship between ABO blood group and CRC are not sufficiently illustrative. Our study focused on the rare subtype of SRCC and revealed for the first time that blood group A and blood group B were independent factors contributing to the poor prognosis of SRCC by univariate and multivariate Cox proportional hazards models.
Lastly, due to the rarity of the subtype, genomic alteration data in SRCC are scarce. However, SRCC, as a subtype that is not sufficiently sensitive to radiotherapy23 and has extremely rapid progression and poor prognosis, urgently needs to be studied in depth. Colorectal SRCC is significantly associated with more peritoneal metastasis, lower KRAS or BRAF mutation rate24, lower E-cadherin expression25, 26 and more MUC2 expression27 than AC, but some studies have shown that BRAF mutation must be closely associated with the presence of malignant signet ring cells regardless of their percentages28. Although previous studies show that SRCC and AC have different genetic features, it is still difficult to fully understand SRCC due to lack of multi-omics analyses. No clinical guidelines has been developed specifically for this entity, it is necessary to reveal the molecular features for guiding the prognosis and precise treatment of colorectal SRCC patients. Here we comprehensively analyzed clinical and genomic data of 64 cases of SRCC from our center. Our results showed that the high frequency mutations of blood group O were TP53, ATM, HLA-I while those of blood group A were KRAS and ALK. KRAS mutations influence multiple pathways including the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways, which regulate cell cycle, promote cell growth and suppress apoptosis, and play a key role in carcinogenesis by inducing an array of inflammatory cytokines, chemokines and accentuates tumorigenesis and invasiveness29. The impact of KRAS mutations might explain the prognosis of patients with blood group A. Patients with blood group O had a higher TMB than others. HLA-I has been extensively used as a biomarker for immunotherapy, and its heterozygous has been associated with disease progression30. Immunotherapy benefits some patients with metastatic cancers, However, so far, only 20%-40% of tumor patients have responded to immunotherapy31, 32. PD-1 antibody gains regulatory approval for the treatment of dMMR/MSI-H metastatic CRC in 2017. In addition, patients with high TMB have higher response rate and longer survival time on PD-1 inhibitor therapy across multiple cancer types33. HLA-I heterozygous mutation is associated with TMB and the HLA-corrected TMB can help to identify patients who do not respond to immune checkpoint inhibitors (ICIs) despite having a high TMB34. Previous reports have shown that HLA-I homozygosity and low mutation burden were strongly associated with decreased survival compared to patients who were heterozygous at each class I locus and the combined effect of HLA class I heterozygosity and TMB on improved survival was greater compared with TMB alone30, 35. They identified three alleles, as possessing a structural bridge in the peptide-binding groove (Arg62, Ile66, and Leu163), and the specific structural feature might modulate the effective T cell recognition of neoepitopes presented on HLA. Our results also showed that SRCC patients who were heterozygous at each HLA class I locus had better prognosis and they belonged to blood group O. Moreover, patient O10 with HLA-I heterozygous mutation, survived more than 10 years after receiving the left hemicolectomy, appropriate chemotherapy and 12 doses of immunotherapy (Sintilimab Injection). Our study revealed for the first time the differences in clinical features and molecular profiles of SRCC in different ABO blood groups. We performed exon sequencing in 21 cases of SRCC and found that patients with blood group O had the potential to benefit from immunotherapy, and that people with A and B blood groups were at high risk of poor prognosis of SRCC. Due to the limitation of the sample size of this project, more studies are needed to prove the findings, and we expect more investigators to focus on this aggressive histological type.
In conclusion, our study revealed different clinical features and molecular profiles of SRCC in different ABO blood groups. Patients with blood group A with high frequency KRAS mutations and patients with blood group B with anemia and metabolic abnormalities had worse OS and needed targeted treatment. Furthermore, some clinical variables such as PT and INR were put forward to predict prognosis of SRCC. Finally, we also delineated SRCC patients with blood group O were heterozygous at each HLA class I locus and had better prognosis. Blood group O might be a novel target for immunotherapy of colorectal SRCC.