Mutational Landscape of Homologous Recombination Deficiency Pathogenic Gene Variants in Colorectal Cancer

At the 2023 World Congress on Gastrointestinal Cancers, Muhammad Danyal Ahsan, New York Presbyterian Hospital, Weill Cornell Medicine, New York, New York, discusses results from a study that utilized the GENIE database to determine the potential utility of widespread functional homologous recombination deficiency status assessment in colorectal cancer.

Ahsan concluded, “These data are hypothesis-generating for studies to specifically evaluate the significance of homologous recombination deficiency amongst colorectal tumors.”

Transcript:

Hi, my name is Danyal Ahsan, and I'm at the ESMO World GI Congress 2023. I just presented an abstract entitled the landscape of homologous recombination deficiency in colorectal cancer.

Homologous recombination deficiency is a pathway for double-stranded DNA repair. Tumors deficient in this pathway can be therapeutically targeted when other pathways for DNA repair are inhibited with drugs such as poly (ADP-ribose) phosphate inhibitors, also known as PARP inhibitors. The current landscape for homologous recombination deficiency in colorectal cancer is largely unknown with sparse literature, so we sought to explore this using the American Association for Cancer Research's GENIE database, which is a multi-institutional, publicly available database with next-gen sequencing profiles for a variety of tumor types. We query the same database for colorectal cancer tumors and querying it for about 27 genes involved in the homologous recombination deficiency pathway. We also explored co-occurrence of gene mutations with mismatch repair mutations, which are more well-known in colorectal tumors, and what we found is, amongst about 15,000 colorectal tumors available on the GENIE database, around 15.1% had pathogenic gene variants in at least one HRD gene. Furthermore, HRD gene mutations tended to co-occur with MMR mutations. Tumors with at least one HRD mutation were about four times as frequent in tumors that also had at least one MMR mutation.

Ultimately, what we found is a relatively high prevalence of somatic HRD mutations in colorectal tumors. So, this has a few implications for research and clinical practice. Firstly, from a therapeutic standpoint, HRD testing could perhaps be more widespread amongst colorectal tumors, and secondly, clinical trials might be warranted to explore the efficacy of PARP inhibitors in a population of people with colorectal cancers. Secondly, from a preventative standpoint, these data are also hypothesis-generating to explore whether colorectal cancer might be a phenotype of the hereditary breast and ovarian cancer syndrome.

Our data have the same limitations as many other large database studies. In this particular case, there was a lack of clinical outcome data, and more importantly, the GENIE database does not give you an ability to assess functional HRD status, which is ultimately what would drive response to therapy. These data are hypothesis-generating for studies to specifically evaluate the significance of homologous recombination deficiency amongst colorectal tumors. Thank you very much for your attention.

Source:

Ahsan M, Bar-Mashiah A, Webster E, et al. The landscape of homologous recombination deficiency in colorectal cancer. Presented at the 2023 World Congress on Gastrointestinal Cancers; June 28-July 1, 2023; Barcelona, Spain. Abstract SO-20