Inherited Risk in Ovarian Cancer: New Genetic Discoveries

Ovarian cancer, particularly high-grade serous epithelial ovarian cancer, is a common cancer in women and is usually diagnosed at an advanced stage. This limits treatment options and increases the importance of early detection. Although genetic factors are known to play an important role in its development, almost half of inherited risk remains unexplained. In other words, some genetic changes or mutations contributing to the development of this cancer have not yet been fully identified.

Dr. Deepak Subramanian and colleagues at the Peter MacCallum Cancer Centre in Melbourne conducted a new study to understand these unknown genetic risks. npj Genomic Medicine published the study on 10 January 2025, identifying new inherited genes that may be associated with high-grade serous ovarian cancer.

New Genetic Discoveries

The researchers analyzed DNA from BRCA1 and BRCA2 mutation non-carriers who had high-grade serous ovarian cancer. Earlier studies had suggested that some gene changes could be inherited and cause cancer. The researchers expanded their genetic analyses to verify these findings and identify new candidate genes as part of this study.

The researchers confirmed that PALB2 and ATM play a role in some cases of inherited ovarian cancer. They also discovered that a new gene called LLGL2 may increase ovarian cancer risk.

• PALB2 and ATM: These genes, already known to be associated with breast cancer, were also shown to play an important role in ovarian cancer risk. In patients with ovarian cancer carrying PALB2 mutations, both alleles were found to be inactivated in the tumors, which could contribute to cancer development. Both alleles of ATM were inactivated in most patients carrying mutations in this gene, although this was not seen in every case. ATM was therefore considered a moderate risk factor for ovarian cancer.
• LLGL2: One of the study's most notable findings was that LLGL2 may be a new inherited risk factor. Both alleles were found to be inactivated in all tumors carrying a mutation in this gene. LLGL2 regulates cell division and cell polarity, and disruption of these functions was thought to contribute to cancer.

The Venn diagram below illustrates the classification of genetic alterations associated with high-grade serous ovarian cancer into different categories .

Categories in the Diagram

1. Wildtype Lost or Inactivated (Green Area)

   • PALB2, LLGL2, VSIG1, LTBP1 and similar genes have lost their wildtype form or become inactivated in tumors.
   • These are likely to be tumor suppressor genes, and loss of their function may contribute to cancer development.

2. Variant Lost or Inactivated (Purple Area)

   • CPT1B, WRAP53, RASSF7, ANKRD18A and similar genes show loss or inactivation of mutation-carrying variants in tumors.
   • Mutations in these genes may be regarded as changes that could play a role in cancer development.

3. Heterozygous or Indeterminate (Blue Area)

   • ATM, FANCM, MAP6D1, STARD6, IFIT2 and similar genes have heterozygous or indeterminate status in the analysis.
   • Their effect on cancer has not been clearly established, although they may have an effect in some circumstances.

Overlapping Areas: Genes in Multiple Categories

• Wildtype Lost or Inactivated & Variant Lost or Inactivated (Green-Purple Overlap)

  • LOXL2, GPALPP1, CDKL3, FAM216A and similar genes show both wildtype loss and loss of the mutated variant.

• Wildtype Lost or Inactivated & Heterozygous or Indeterminate (Green-Blue Overlap)

  • ATM, FANCM, MAP6D1, SCYL3 and similar genes may show wildtype loss while also having heterozygous or indeterminate status.

• Variant Lost or Inactivated & Heterozygous or Indeterminate (Purple-Blue Overlap)

  • ERCC3, SORD, SSX3, IMPDH2 and similar genes may show variant loss while also having heterozygous or indeterminate status.

• Triple Overlap: The Central Area

  • BLM, SLC12A4, ZBTB45, ZCCHC4, RAD1 and similar genes partly fall into all categories and may contribute to cancer development through different mechanisms.

Conclusion and Future Perspectives

This study represents an important advance in understanding ovarian cancer genetics. The researchers suggest that PALB2, ATM and LLGL2 may be associated with high-grade serous ovarian cancer and could be critical for early detection, risk assessment and future targeted treatments.

These findings will help improve our understanding of the genetic basis of ovarian cancer and support better diagnostic tests and cancer risk classification.

Identifying these genes could improve diagnosis and contribute to targeted treatment strategies. In particular, identifying LLGL2 as a new cancer risk factor requires further research. A better understanding of its functions could make important contributions to personalized medicine.