somatic mutation

**Definition:** A somatic mutation is an alteration in DNA sequence or structure that arises in a somatic (non-gamete) cell after conception. It is present only in that cell and its clonal descendants. It is not inherited by offspring, unlike a germline mutation, which is present in every cell and passed on through gametes.

**Causes:** - Replication errors, especially when mismatch repair (MMR) is defective, as in Lynch syndrome. - Environmental mutagens: UV light (pyrimidine dimers, as in skin cancer and xeroderma pigmentosum), tobacco carcinogens, aflatoxin (TP53 mutation in hepatocellular carcinoma), and ionizing radiation. - Spontaneous chemical changes: deamination of cytosine or 5-methylcytosine, depurination, and oxidative damage. - Chromosomal rearrangements: translocations such as t(9;22) BCR-ABL (CML) and t(8;14) c-MYC (Burkitt lymphoma).

**Types:** point mutations (silent, missense, nonsense), frameshift insertions/deletions, copy-number changes and amplifications (HER2 or N-MYC), and translocations.

**Cancer relevance:** - Oncogenes (gain of function, dominant at the cell level): RAS, BRAF V600E (melanoma, hairy cell leukemia), JAK2 V617F (polycythemia vera, ET, PMF), EGFR (lung adenocarcinoma), KIT (GIST), BCR-ABL, HER2. - Tumor suppressors (loss of function, usually need both alleles inactivated): TP53, RB, APC, PTEN, BRCA1/2. - Knudson two-hit hypothesis: sporadic cancers need two somatic hits. Hereditary cancers inherit one germline hit and acquire the second somatically, so they appear earlier, are often bilateral or multifocal, and run in families. - Driver mutations confer a growth advantage. Passenger mutations are incidental. - Multistep carcinogenesis: the adenoma-carcinoma sequence in colon cancer (APC → KRAS → SMAD4/DCC → TP53).

**Other clinical examples:** - Mosaicism: a somatic mutation early in embryogenesis gives a patchy phenotype. Examples are McCune-Albright syndrome (GNAS activating mutation, with polyostotic fibrous dysplasia, café-au-lait spots, and endocrinopathies) and Sturge-Weber syndrome (GNAQ). - Paroxysmal nocturnal hemoglobinuria: an acquired somatic PIGA mutation in a hematopoietic stem cell. It causes a GPI-anchor defect and loss of CD55/CD59, leading to complement-mediated hemolysis. PIGA is X-linked, so only one hit is needed. - Clonal hematopoiesis of indeterminate potential (CHIP): somatic mutations in DNMT3A, TET2, and ASXL1 are associated with a higher risk of hematologic malignancy and cardiovascular disease. - Somatic hypermutation and V(D)J recombination in B cells are physiologic somatic changes that generate antibody diversity.

**Testing and therapy:** Tumor sequencing identifies targetable somatic mutations. Examples include imatinib for BCR-ABL and KIT, vemurafenib for BRAF V600E, osimertinib or erlotinib for EGFR, and trastuzumab for HER2. Sequencing is also used for prognosis and for monitoring resistance mutations such as EGFR T790M.

**High-yield contrast:** | | Somatic | Germline | |---|---|---| | Cell affected | Body cells | Gametes, so all cells in the offspring | | Heritable | No | Yes | | Typical disease | Sporadic cancer | Hereditary syndromes (Li-Fraumeni, FAP, BRCA) | | Presentation | Later onset, unifocal | Earlier onset, multifocal, family history |

**Exam pearl:** A tumor-only mutation found on sequencing is somatic. If a variant is also present in normal tissue such as blood, think germline, and consider genetic counseling and testing of relatives.