Loss of two genes may drive serrated colorectal cancers

Two genetic markers linked to an aggressive, treatment-resistant form of colorectal cancer.

Serrated tumours are harder to treat than other colorectal cancers, and clinicians frequently struggle to differentiate between serrated and non-serrated tumours. More than a third of colorectal cancers arise from serrated polyps in the colon.

'Our study identified two genetic markers that may clearly identify this colon cancer subgroup and offer an effective precision medicine treatment option,' said study author Dr Darren Sigal, program director of gastrointestinal oncology at Scripps MD Anderson Cancer Center.

The researchers identified the genes in experiments in mice. When mice lacked two genes – which encode protein kinase C lambda/iota and protein kinase C zeta – they spontaneously developed serrated colorectal cancer. Human tissue samples from colorectal cancer patients also showed lowered expression of these proteins compared with samples from cancer-free people.

As well as finding a biomarker for serrated colorectal cancer, the researchers also found a potential treatment combination that could tackle the condition.

Losing the two genes led to a protein called PD-L1 infiltrating the tissue surrounding a serrated tumour. This protein is known to mask cancerous cells from immune cells. When the researchers applied two compounds – TGF-beta receptor inhibitor and anti-PD-L1 – to the tumours, the PD-L1 levels decreased and immune response improved.

'Our findings identify both a promising combination treatment for serrated colorectal cancer and potential biomarkers that can identify this cancer subtype – both of which are urgently needed,' says Dr Jorge Moscat, study author and director and professor in Sanford Burnam Prebys's Cancer Metabolism and Signaling Networks Program.

'Additionally, the mouse model we created closely mirrors the human disease, an important step that could help reveal more insights into this deadly cancer.'

The research was published in the journal Immunity.