Cancer predisposition syndromes (CPS) account for an estimated 8% to 15% of pediatric malignancies. For surgeons taking care of children, adolescents, or young adults with childhood cancers, familiarity with these syndromes is essential. Recognition of a CPS can alter surgical decision-making, guide screening of at-risk family members, and inform long-term surveillance. This review provides an overview of the genetic basis of the most common pediatric solid tumors encountered by the general surgeon, including renal tumors, neuroblastoma, hepatic tumors, soft tissue and bone sarcomas, thoracic tumors, abdominal tumors, colorectal cancer, melanoma, and tumors of infancy.

Sarcoma genetics carries important clinical implications for the screening, diagnosis, and management of patients and their families. However, most sarcomas develop sporadically. Management of patients with hereditary sarcoma syndromes is complex and requires lifelong surveillance and multi-disciplinary care to minimize death from cancer and to maximize quality of life preservation.

Prostate cancer is a highly prevalent and heritable malignancy with marked disparities in incidence, stage at diagnosis, and mortality among minority populations. While localized disease carries an excellent prognosis, outcomes decline sharply in advanced and metastatic cases, underscoring the need for improved risk stratification. This article reviews the role of germline and somatic genetic alterations in prostate cancer development, prognosis, and treatment selection. It outlines current guideline-based indications for genetic testing, emerging evidence supporting broader testing strategies, and evolving tools including polygenic risk scores, tumor-derived genomic classifiers, digital histopathology platforms, and circulating tumor DNA.

Advances in cancer genomics have transformed the prevention, classification, and management of gynecologic malignancies. Germline and somatic genetic alterations now inform hereditary cancer risk assessment, molecular tumor classification, and selection of targeted and immune-based therapies. Syndromes such as BRCA-associated hereditary breast and ovarian cancer and Lynch syndrome guide surveillance, cascade testing, and risk-reducing surgery. Molecular frameworks, including The Cancer Genome Atlas classification in endometrial cancer, refine prognosis and treatment intensity. Biomarker-driven therapies-such as poly (ADP-ribose) polymerase inhibitors, immune checkpoint inhibitors, and HER2-directed agents-have become integral across disease stages.

Malignant melanoma represents a lethal cutaneous malignancy. This review article highlights somatic mutations as well as high- and moderate-penetrance germline genetic mutations frequently found in melanoma. BRAF and CDKN2A remain the most frequently identified somatic and germline mutations respectively; however, numerous others have been implicated including KRAS, c-KIT, CDK4, BAP1, TERT, POT1, ACD/TERF2IP and ATM. Approximately half of patients with familial melanoma syndrome do not have clearly identified or documented mutations. Thus, screening recommendations vary and polygenic risk scoring systems aid in personalized risk stratification and screening approaches. Collectively, this review synthesizes genetic insights to support precision-based clinical decision making.

Management of adrenal tumors and neuroendocrine tumors (NETs) requires careful discussion on whether resection with curative intent is worth the risk of surgical morbidity and risk of endocrine morbidity requiring exogenous hormonal replacement. Such deliberations are important in germline-associated NETs and adrenal tumors because of the multifocal nature of the disease. Identifying patients with germline mutations will encourage screening and surveillance to be more frequent compared to patients with sporadic-associated mutations. With improvements in molecular profiling, mutational patterns are more efficiently detected, allowing for more individualized treatment plans and potential future targeted therapies.

Pancreatic cancer is a highly lethal malignancy with an overall 5-year survival rate of just 13%, and its most common histologic subtype, pancreatic ductal adenocarcinoma (PDAC), carries an even poorer prognosis. Its aggressive nature is driven by complex genetic, epigenetic, and microenvironmental alterations. Key driver mutations in Kirsten rat sarcoma, cyclin-dependent kinase inhibitor 2A, TP53, and SMAD4 promote tumorigenesis, genomic instability, and resistance to therapy. Advances in molecular profiling have improved the understanding of PDAC biology, identifying actionable mutations and therapeutic targets. Despite progress, effective targeted therapies remain limited, and early metastasis continues to hinder outcomes. Ongoing research aims to refine patient selection and optimize treatments.

There are 3 known hereditary gastric cancers that contribute to 1% to 3% of all gastric malignancies: hereditary diffuse gastric cancer, gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. Additional hereditary cancer syndromes also contribute to increased lifetime risks of gastric malignancies: hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Peutz-Jeghers, Li-Fraumeni, and juvenile polyposis syndrome. Germline mutations in DNA damage repair genes may be contributing to the pathogenesis of gastric cancer and may be a target for future therapeutic modalities.

Inherited thyroid and parathyroid diseases represent a small but clinically significant subset of endocrine neoplasms, often associated with identifiable genetic mutations. Familial medullary thyroid cancer is linked to RET mutations and frequently occurs with multiple endocrine neoplasia syndromes, requiring early diagnosis and prophylactic intervention. Nonmedullary familial thyroid cancers are more heterogenous with unclear genetic drivers and variable inheritance patterns. Syndromic forms carry increased thyroid cancer risk necessitating targeted surveillance. Familial parathyroid disease presents earlier than sporadic disease and carries important implications for management and surveillance. Comprehensive clinical evaluation, risk stratification, and family screening are essential for optimal management and outcomes.

Colorectal cancer (CRC) genetics carries important clinical implications for the screening, diagnosis, and management of patients and their families. All CRCs should undergo universal tumor screening, preoperatively whenever possible, to assess for mismatch repair deficiency. Additionally, germline genetic testing plays an integral role in diagnosing polyposis and nonpolyposis hereditary CRC syndromes; therefore, understanding genetic testing criteria is critical to identify patients with these syndromes. Management of patients with hereditary CRC syndromes is complex and requires lifelong surveillance and multidisciplinary care to minimize death from cancer and to maximize quality-of-life preservation.

This clinical review guides general surgeons in breast cancer genetics, risk assessment, screening, risk-reducing strategies, outlining evaluation and management strategies for average-risk and high-risk women using models like Gail and Tyrer-Cuzick, reviews indications for genetic testing, and interpretation of results. Evidence-based screening approaches-including mammography, MRI, contrast-enhanced mammography, ultrasound, and molecular breast imaging-are reviewed, highlighting benefits and limitations of supplemental diagnostic imaging. Risk-reducing interventions are discussed with emphasis on mutation status, family history, and individualized patient care. The review equips surgeons to integrate genetics into prevention, early detection, and tailored management strategies for breast cancer.