Abstract
The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.
Highlights
Laboratory genetic techniques achieved reasonable compatibility with a daily clinical practice as early as in 1980s, mainly due to the invention and rapid implementation of polymerase chain reaction (PCR) [1] and Sanger sequencing [2]
The first medical applications of DNA analysis involved the diagnosis of hereditary disorders [3], PCR-based detection of bacteria and viruses [4], genetic testing of various disease-specific rearrangements in leukemia patients [5] and HLA genotyping for organ donors and recipients [6]
Expression by immunohistochemistry (IHC); subsequent analysis of disease outcomes revealed no relevance of EGFR status in tumor response, RAS mutations emerged as a strong predictor of tumor resistance to cetuximab or panitumumab [9,10]
Summary
Laboratory genetic techniques achieved reasonable compatibility with a daily clinical practice as early as in 1980s, mainly due to the invention and rapid implementation of polymerase chain reaction (PCR) [1] and Sanger sequencing [2]. The first medical applications of DNA analysis involved the diagnosis of hereditary disorders (including familial cancer syndromes) [3], PCR-based detection of bacteria and viruses [4], genetic testing of various disease-specific rearrangements in leukemia patients [5] and HLA genotyping for organ donors and recipients [6]. Only a few cancer patients included in the clinical trials responded to EGFRi; a posteriori analysis of responders revealed drug-sensitizing mutations in the NSCLC tissue, which were unknown at the time of the drug’s development [7]. Some predictive DNA tests provide integrative characteristics of the cancer genome, e.g., they indicate at high tumor antigenicity due to an excessive number of mutations or druggable deficiency of DNA repair.
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