Identify putative drugs and pertubagens that selectively sensitize specific cancer cell lines for translational cancer research

Q&A
, ,
1

Dear DepMap Community Forum,

good afternoon and I hope my message finds you well and healthy !!

Briefly, based on an international collaborative research project (Athens Comprehensive Cancer Center (ACCC)) regarding colorectal cancer, our major goal is to investigate, if there any specific functional programs in specific clinical groups of patients, that might interrelate the presence of specific mutational patterns (KRASonly, BRAFonly and wild type), as the ultimate goal is to investigate the molecular landscape of these 3 defined groups-we also utilize additionally public TCGA data to enhance our sample size-

Ultimately, based on my major post-doc project, I would like to use the DepMap portal data, in order:

A) Compare if possible KRAS-mutated cell lines versus other colorectal cancer cell lines without the KRAS mutation; the same approach also to be extended to BRAF-mutated cell lines, even to expand to specific allele-mutated samples based on the availability

B) In detail, my main goal is to identify which perturbagens/drugs might sensitize differentially these groups of cell lines, that could be associated with distinct clinical subgroups; in addition, which genes are mainly affected and/or altered in each group-this might give us an additional external validation, as from our gene expression data, we have identified separate gene signatures for each group (KRAS mut, BRAF mut etc.) and thus prioritize further specific targets;

  1. On this premise, from the data portal, one approach would be to use the Custom analyses section, and utilize the 2-group comparison; however, is it possible for the data portal to find information for mutational status concerning colorectal cancer cell lines? In order to perform an appropriate selection and robust creation of the compared cell lines? Or I would have to use another portal?

  2. Furthermore, as the second aim to identify the genetic dependencies-i.e. the genes-that are mostly correlated with the above drug sensitivity profiles, the most direct and robust approach would be to select from the step1 the top perturbagens, and perform a correlation analysis?

Thank you in advance for your time and consideration on this matter!!

With Kind Regards,

Efstathios-Iason

2

Regarding #1, you can use cell line selector to identify colorectal cancer cell lines and add a column for mutational status, and then use that to filter your set down. However, when you say “mutational status” I’m not what resolution you are looking for.

We have a simple binary flag for a few mutational classes (has a hot spot mutation, has a damaging mutation, has a nonconserving mutation, etc) that you can add as a column in cell line selector. If you wanted to look for specific mutations or a more nuanced calling for how your KRAS-mut class is defined, you won’t be able to see that within cell line selector.

1 Like
3

Dear @pmontgom,

thank you very much for your initial answer and prompt explanation, especially regarding cell line selector;

in addition, apologies for not providing a more detailed description of my project goal regarding the “mutational status”;

based on the initial clinical cohort of 33 colorectal cancer patients sequenced, we have separated the patients based on the 3 aforementioned groups:

KRAS_mutated= include protein mutations G12D, G12S, G12V and A146V

BRAF_V600E mutated patients

BRAF_Other= which includes other distinct BRAF alterations

and WT, which includes patients with no KRAS or BRAF mutations

Thus, my initial approach for my post-doc project-in order to utilize the DepMap portal-is to find colorectal cell lines, and separate the cell lines based on the above mutations if possible(and available sample size at least 3 samples per condition) and then perform the comparisons I have mentioned-on this direction, based on your instructions, I tried an initial approach with Cell line selector, and my updated questions on this direction:

CellLineSelector.Test
CellLineSelector.Test2352Ă—1184 255 KB

  1. As you mentioned, I can select based on Lineage as “colorectal”, and then in the AddColumn section to add mutational information for KRAS and BRAF gene mutations, correct?

  2. As you pinpointed, this information does not include specific mutations, such as my above mentioned, in order to somehow stricter the “mutational spectrum” right? And the only way to further restrict my selection, is to initially check which colorectal cell lines have for example a KRAS mutation, and then go and check in each cell line page in the mutation tab, as in the following figure?

mutations.sel
mutations.sel2333Ă—522 41.3 KB

  1. In addition, you also mentioned about a simple binary flag for a few mutational classes (has a hot spot mutation, has a damaging mutation, has a nonconserving mutation, etc.)-is there a link or publication for a further explanation concerning each “flag”? For example, in my case as I have WES data and focused on protein-coding mutations, I could exclude cell lines with nonconserving mutation? Or has a different translation?

  2. Finally, based on each cell line information and DepMap portal utilization, I would like to ask you an extra crucial question: in each page of each cell line, there is a small tag called:

"Top 10 preferentially essential genes (CRISPR DepMap 21Q2 Public + Score, CERES)-as based on a further discussion with our collaborators, they asked me if possible from the data portal, to expand this list of top10 genes to a larger gene of essential genes: our ultimate goal, is to create a list of essential genes for colorectal cancer, in order to assign a further weight/score in our variant prioritization approach, further promoting mutations which are found in genes essential in colorectal cancer cell lines;

thus, which dataset should I download and utilize, aiming to create a “compendium” of essential genes for CRC?

Thank you in advance for your effort and help !!

Best regards,

Efstathios