Hereditary cancer syndromes.

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Hereditary cancer syndromes (HCSs) are common Mendelian diseases, with over 2% of healthy individuals carrying high-penetrance tumor-predisposing variants (PVs).
• Hereditary breast-ovarian cancer and Lynch syndrome are major contributors to cancer morbidity, alongside numerous other familial tumor types.
• The development of most hereditary cancers involves a two-hit mechanism, typically somatic inactivation of the remaining gene copy.

Purpose of the Study:

• To review the current understanding of hereditary cancer syndromes, focusing on penetrance, genetic mechanisms, and therapeutic advancements.
• To highlight the shift in research focus from cancer detection and prevention to identifying and exploiting HCS-specific drug vulnerabilities.

Main Methods:

• Review of population-based studies and large-scale next-generation sequencing data.
• Analysis of genetic penetrance of pathogenic variants (PVs) in hereditary cancer syndromes.
• Examination of recent therapeutic strategies targeting HCS-specific vulnerabilities.

Main Results:

• Contrary to earlier assumptions, many highly-penetrant PVs are compatible with a healthy status.
• Next-generation sequencing data reveal a broader spectrum of penetrance for HCS genes than previously thought.
• Identification of HCS-specific drug vulnerabilities has led to the development of effective therapeutic options.

Conclusions:

• Hereditary cancer syndromes represent a significant genetic disease category with variable penetrance.
• The understanding of HCSs has evolved, with a growing emphasis on targeted therapies based on identified drug vulnerabilities.
• Advances in genetic sequencing and molecular biology are paving the way for more effective treatments for hereditary cancers.