What are the key germline and somatic genetic alterations in breast and ovarian cancer, colorectal cancer, non‑small‑cell lung cancer, melanoma, pancreatic ductal adenocarcinoma, and acute myeloid leukemia, and how do they inform targeted therapy?

Genetic Basis of Selected Cancers

Understanding both germline and somatic genetic alterations is essential for guiding targeted therapy and improving outcomes in cancer patients, with high-penetrance germline mutations (BRCA1/BRCA2, TP53, PTEN, MLH1/MSH2/MSH6/PMS2, APC, CDH1, STK11) conferring the highest cancer risk and requiring the most aggressive surveillance and prophylactic measures. 1

Germline vs. Somatic Alterations: Critical Distinctions

High-Penetrance Germline Mutations

• BRCA1/BRCA2, TP53, PTEN, MLH1/MSH2/MSH6/PMS2, APC, CDH1, and STK11 represent the well-established high-penetrance genes that cause substantially elevated cancer risk and warrant prophylactic interventions rather than just enhanced screening. 1
• These germline mutations have lifelong implications for affected individuals and multiple family members, requiring cascade genetic testing of relatives. 1
• Approximately 3-12.6% of adult cancer patients harbor actionable pathogenic germline variants when unselected cohorts undergo tumor-normal sequencing. 1

Moderate-Penetrance Germline Mutations

• ATM, CHEK2, and PMS2 confer more modest cancer risk (relative risk 2-5) compared to high-penetrance genes. 1
• Management differs significantly: moderate-penetrance mutations typically warrant earlier disease screening rather than prophylactic surgeries. 1
• PALB2 mutations are well-established for increased breast and pancreatic cancer risk, though the association with ovarian cancer remains statistically unproven despite some suggestive studies. 1

Cancer-Specific Genetic Alterations

Breast and Ovarian Cancer

• Germline BRCA1/BRCA2 mutations account for approximately 5% of ovarian cancers, with all BRCA1-associated ovarian cancers demonstrating loss of heterozygosity at the BRCA1 locus. 2
• Somatic BRCA1 mutations also occur in sporadic ovarian cancer cases, and like germline mutations, are accompanied by loss of the wild-type allele, suggesting loss of this tumor suppressor is critical for cancer development. 2
• Up to 10% of breast cancers are hereditary forms caused by inherited germline mutations in high-, moderate-, and low-penetrance susceptibility genes, while 90% result from acquired somatic genetic and epigenetic alterations. 3
• Promoter hypermethylation of DNA repair genes and hormone-signaling genes, plus altered microRNA expression, play equally important roles as genetic factors in breast cancer development. 3

Colorectal Cancer

• Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) can harbor either somatic or germline mutations in microsatellite-unstable tumors, making germline confirmation essential to establish hereditary cancer syndrome diagnosis. 1
• APC truncating mutations are highly penetrant for familial adenomatous polyposis (FAP), though specific variants like the Ashkenazi Jewish APC p.Ile1307Lys confer only moderate penetrance. 1
• POLD1 predisposes to colorectal adenomas and carcinomas but may not be included in all somatic sequencing panels. 1

Pancreatic Cancer

• PALB2 germline mutations confer established increased risk for pancreatic ductal adenocarcinoma in addition to breast cancer. 1

Melanoma and Lung Cancer

• The provided evidence does not contain specific genetic alterations for melanoma or non-small-cell lung cancer beyond general principles of somatic driver mutations.

Acute Myeloid Leukemia

• EZH2 loss-of-function variants play a tumor suppressive role specifically in myeloid malignancies, illustrating the importance of tumor-type context when interpreting genetic alterations. 1

Clinical Implications for Targeted Therapy

Therapeutic Targeting Based on Germline Findings

• Germline mutations in homologous recombination and DNA repair genes (BRCA1/BRCA2) confer sensitivity to PARP inhibitors and platinum-based chemotherapies, making germline testing therapeutically actionable for the affected patient, not just family members. 1
• In one cohort, 21% (38 of 182) of patients with pathogenic germline variants had documented therapy discussions or initiation based on germline findings at 1-year follow-up. 1
• Germline defects in mismatch repair genes may be targetable with immune checkpoint blockade, similar to somatic and epigenetic alterations in these pathways. 1

Somatic Alterations and Treatment Selection

• BRAF p.Val600Glu demonstrates oncogenic effects with therapeutic implications across multiple malignancies, though this same variant causes embryonic lethality in the germline context. 1
• TERT alterations differ dramatically by context: oncogenic TERT changes in sporadic malignancies are typically copy number gains and promoter variants increasing expression, while germline TERT pathogenic variants are loss-of-function events. 1

Tumor-Normal Sequencing: The Gold Standard Approach

Why Paired Sequencing Matters

• Tumor-only sequencing cannot distinguish somatic mutations from germline variants, creating ambiguity about whether detected changes represent targetable somatic drivers or inherited cancer susceptibility. 1
• Sequencing both tumor and matched normal tissue definitively identifies somatic variants by filtering out germline changes, ensuring all reported variants represent potentially targetable somatic alterations. 1

Panel Design Considerations

• Somatic sequencing panels designed for therapeutic purposes may not encompass all hereditary cancer predisposition genes, limiting sensitivity of secondary germline analysis. 1
• Comprehensive panels should include ACMG-recommended genes for secondary findings plus all known hereditary cancer predisposition genes when germline analysis is intended, even if these genes lack somatic implications. 1
• Missing genes like PMS2, PALB2, HOXB13, or POLD1 from panels reduces the comprehensiveness of germline screening, though tumor-normal sequencing remains an extremely sensitive screening test. 1

Critical Pitfalls and Caveats

Variants of Uncertain Significance (VUS)

• Routine clinical decisions should never be based on VUS, though these variants may inform therapeutic interventions in well-documented trials at high-volume academic centers. 1
• VUS inclusion in clinical trials requires careful review of the variant, tumor type molecular drivers, therapeutic alternatives, patient performance status, and comprehensive informed consent. 1

Context-Dependent Interpretation

• The same genetic variant can have completely different implications in germline versus somatic contexts, requiring careful interpretation based on tumor type and molecular biology. 1
• Some variants provide tumor cells with stress tolerance or limited growth advantage during early neoplasm development rather than classical oncogenic effects, yet remain relevant for oncogenesis. 1

Germline Confirmation Requirements

• When clinically relevant variants are detected during tumor-only sequencing, follow-up germline testing should be considered to confirm germline versus somatic origin when clinical implications differ significantly. 1
• Informatics approaches to infer germline origin from tumor sequencing are imperfect and can both filter out true somatic alterations and miss germline variants. 1

Impact on Somatic Tumor Biology

• Higher polygenic risk scores associate with earlier cancer onset and lower burden of somatic alterations, including fewer total mutations and chromosomal copy-number alterations, contrasting with rare germline pathogenic variants that show heterogeneous associations. 4
• This suggests common germline cancer risk variants enable early tumor development before accumulation of the many somatic alterations characteristic of later carcinogenesis stages. 4
• Germline variants can impact the selection and generation of specific somatic mutations during tumorigenesis, influencing cancer subtypes, treatment response, and clinical outcomes. 5