Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome

Abstract

Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour-distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA-sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour-promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours.

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

“…Despite some differences, MLH1 -/- mice combine several key features of both syndromes. The recently detected heterogeneity of Lynch-associated cancers, being highly immunogenic or not (25), additionally argues in favor of using these mice as a model for Lynch Syndrome as well. All malignant human CMMR-D cancers are ultra-hypermutated.…”

Immunoprofiles of colorectal cancer from Lynch syndrome

“…Already during the early adenoma stage, the immune microenvironment may direct immune system attacks. 36 In tissues highly infiltrated with immune cells, tumors may develop through an early loss of B2M heterozygosity that allows for survival in a highly immunogenic environment (Figure 3). Subgroup analyses linked B2M loss with low levels of MHC class I related genes supporting previous studies.…”

Lynch syndrome – cancer pathways, heterogeneity and immune escape

“…CD3, CD4, CD8, and CD19), and this is backed up by strong CD4 + staining demonstrated by immunohistochemistry. Moreover, G1 reference mucosa shows higher expression of genes related to MHC antigen presentation and of chemokine receptor–ligand pairs compared with G1 tumours . These data suggest that G1 tumours undergo transcriptional reprogramming to dysregulate the immune response and hence evade immune destruction.…”

“…Further new evidence now supports the contention that, in addition to different precursor lesions, distinct molecular and cellular subtypes of LS‐CRC exist. Binder et al utilised CRC resection specimens from LS patients to demonstrate at least two distinct genetic subtypes of LS‐CRC, termed G1 and G2 . DNA sequencing showed that G1 tumours have a different mutation spectrum to G2 tumours, with higher mutation numbers and greater MSI.…”

“…DNA sequencing showed that G1 tumours have a different mutation spectrum to G2 tumours, with higher mutation numbers and greater MSI. Interestingly, G1 cancers share these characteristics with sporadic MSI CRC, whereas the mutational profile of G2 cancers tends more to resemble that of microsatellite‐stable (MSS) sporadic CRC . Additionally, a higher proportion of G1 cancers arise on a background of germline MLH1 mutation compared with G2 cancers.…”