What are Frameshift Mutations?

Frameshift muta­tions are inser­tions or dele­tions of any num­ber of nuc­le­otides not divis­ible by three. This is due to the fact that nuc­le­otides are read and trans­lated to an amino acid in triplets. These ‘indels’ in the genet­ic code have been linked to a diverse array of dis­eases. Giv­en they dir­ectly cause, the pro­duc­tion of incor­rect pro­teins as well as trun­cated or abnor­mally long pro­teins, their key role in many patho­gen­ic mech­an­isms is unsur­pris­ing.

Frameshift Mutations in Cancer

Mutations in various Cancer Types

Examples of frameshift dis­cov­er­ies in can­cer lead­ing to improved patient care, new treat­ments or great­er under­stand­ing of a dis­ease mech­an­ism are numer­ous. For instance, stud­ies on lung can­cer, melan­oma and ren­al cell car­cinoma described an elev­ated num­ber of frameshift muta­tions to be a very sig­ni­fic­ant indic­at­or of immune check­point inhib­it­or treat­ment response (Chae et al., 2019; Hanna et al., 2018).

Immonogenic Frameshift Peptides

Fur­ther­more, mis­match-repair defi­cient tumors have been found to com­monly har­bor frameshift muta­tions. This can­cer type is marked by vari­ous muta­tions of DNA mis­match repair genes. The induced loss of DNA repair func­tion­al­ity leads to an increase of muta­tions with­in so-called micro-satel­lite regions (often con­sist­ing of repet­it­ive gene sequences). This, in turn, leads to fre­quent frame shift­ing. A recent study showed that tran­scrip­tion errors and exon mis-spli­cing could also lead to the pro­duc­tion of immun­o­gen­ic frameshift pep­tides (Shen et al., 2019). One can expect sev­er­al dis­cov­er­ies of these types of frameshift pep­tides in the future, as they are invest­ig­ated more extens­ively. Pre­sum­ably, some con­di­tions that were pre­vi­ously thought of as unre­lated to frameshift pep­tides may be uncovered as being asso­ci­ated with these. So, it is a great advant­age to include such pep­tides in screen­ing arrays, just as in our engine pro­tein array hEXse­lect.

Neopeptides as reactive Antigens

In a study by Schwit­alle et al. it was found that mis­match-repair defi­cient can­cer patients (MRI‑H can­cers) fre­quently dis­play a high dens­ity of tumor infilt­rat­ing lymph­o­cytes (Sæter­dal et al., 2001). This sup­ports the the­ory that frameshift-neopeptides act as highly react­ive neoanti­gens and evoke a tumor-spe­cif­ic immune response (Schwit­alle et al., 2008). The immune response mark­ers could also be detec­ted in peri­pher­al blood. This facil­it­ates the invest­ig­a­tion of this pro­cess using pro­tein arrays screen­ings. This inher­ent immun­o­gen­i­city of tumor-asso­ci­ated frameshift neopeptides can be exploited to enhance an anti-tumor immune response in patients.

Frameshift mutations as therapeutic input

The great poten­tial of such an approach is high­lighted by the advent of sev­er­al highly effect­ive per­son­al­ized can­cer vac­cines.  In a recent study by Zhang, Shen and John­ston (2019), a pep­tide array plat­form was used for identi­fy­ing tumor frameshift neoanti­gens for the pur­pose of devel­op­ing such per­son­al­ized can­cer vac­cines. They could detect both com­mon react­ive frameshift pro­teins and can­cer-spe­cif­ic immune responses. Using such arrays greatly facil­it­ates the pro­cess of screen­ing for frameshift pep­tides and determ­in­ing what role they play in dif­fer­ent patient groups.