# From Genomics to AI: Revolutionizing Precision Medicine in Oncology
## 2 Genomics in Cancer Diagnosis  
Genomics has significantly contributed to cancer diagnosis by identifying specific genetic alterations that support clinical decision making. Both somatic pathogenic variants (sPVs), which arise in tumor cells, and germline pathogenic variants (gPVs), which are inherited, play a crucial role in cancer development and progression. sPVs occur in the DNA of individual cells and are not transmitted to offspring, typically resulting from environmental factors or errors in DNA replication. gPVs, on the other hand, are present in the DNA of every cell of an individual and can be inherited from one or both parents, predisposing individuals to various types of cancer [11; 12]. PVs are identified using a combination of bioinformatics tools, functional assays, and clinical guidelines, such as those provided by the American College of Medical Genetics and Genomics (ACMG). Criteria include the type of mutation (e.g., nonsense, frameshift), its frequency in the general population, segregation with disease in families, computational predictions, and available experimental or clinical evidence linking the variant to disease [13]. One of the most well-characterized genetic signatures in oncology includes gPVs in _BRCA1_ and _BRCA2_ genes, which confer susceptibility to breast and ovarian cancers, accounting for 5-10% of breast cancer cases and 5-25% of ovarian cases [14]. PVs in _BRCA1_ and _BRCA2_ impair the repair of DNA damage, leading to an accumulation of mutations in cells, thereby increasing the risk of cancer. These gPVs are inherited in an autosomal dominant pattern, meaning an individual with a variant in either gene has a 50% chance of passing it on to their offspring. Additionally, _BRCA_-gPVs not only affect breast and ovarian cancers but also increase the risk of other cancers, such as prostate and pancreatic cancer [15]. Somatic genetic testing of _BRCA1_ and _BRCA2_ is currently employed in breast, ovarian, pancreatic, and prostatic cancers to guide the administration of PARP inhibitor therapy. BRCA1/2 are involved in the homologous recombination DNA repair pathway; their loss leads to homologous recombination deficiency. PARP inhibitors exploit this defect through a mechanism of synthetic lethality, as inhibition of PARP-mediated single-strand break repair leads to the accumulation of DNA damage and subsequent cell death in BRCA-deficient tumor cells [16]. When a PV is identified through somatic testing, patients are often referred for genetic counseling to determine if they are germline mutation carriers. This distinction is crucial, as germline mutation carriers may benefit from advanced screening, risk-reduction strategies, and genetic testing for identifying family members at risk. Other hereditary breast-cancer-associated genes include high-penetrance genes (e.g., _CDH1_, _PALB2_, _PTEN_, _STK11_, _TP53_) and moderate-penetrance genes (e.g., _ATM_, _BARD1_, _BRIP1_, _CHEK2_, _RAD51C_, _RAD51D_), where \"penetrance\" describes the proportion of individuals carrying a pathogenic variant who actually develop the associated disease [17]. Similarly, PVs in _EGFR_ are somatic alterations commonly observed in non-small cell lung cancer (NSCLC). These variants typically occur in the epidermal growth factor receptor gene, which regulates cell growth and survival, and they cause the receptor to be constantly active, promoting tumor cell proliferation. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), specifically inhibit this mutated receptor, offering a more personalized treatment approach for patients with NSCLC [18]. Other key genomic alterations include _KRAS_ variants in colorectal and pancreatic cancers and _TP53_ variants, which are found in a wide range of malignancies and often indicate poor prognosis. _KRAS_ pathogenic variants drive uncontrolled cell proliferation in colorectal and pancreatic cancers, whereas _TP53_ (called the \"guardian of the genome\") pathogenic variants lead to the loss of a crucial tumor suppressor function, increasing metastasis risk [19].