Hereditary epithelial ovarian tumors

# Hereditary epithelial ovarian carcinoma: an overview of hereditary syndromes and the genes mutations

## Hereditary breast and ovarian cancer (HBOC)
- Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant disorder caused by mutations in BRCA1 and BRCA2 genes that are responsible for DNA repair in homologous recombination pathway.
- Individuals with this disorder are at risk of developing breast (lifetime risk is 30-80%) and ovarian cancer (lifetime risk is 30-50%), along with other malignancies such as pancreatic, stomach, laryngeal, fallopian tube and prostate cancer.
- The reason for increased susceptibility to ovarian and epithelial cancer is not fully understood but but may be explained by repression of the transcription of hormone-mediated signalling factors or production of reactive oxygen species during menstrual cycle mediating DNA damage.

## Lynch Syndrome
- Lynch syndrome (LS), also known as hereditary nonpolyposis colon cancer (HNPCC), is characterized by germline mutations in DNA mismatch repair genes MLH1, MSH2, MSH6, MLH3, and PMS2.
- A simplified version of repair mechanism by mismatch repair genes products is described below:
MutS homologs (MSHs) recognize the DNA mismatch  MutS homologs (MSHs) recruit MutL homologs (MLHs)  excision of mismatched DNA  DNA polymerase re-synthesizes DNA.
- Accounted for 10-15% of all ovarian cancers, this syndrome is caused by inherited mutation in one allele and then loss of second allele (secondary hit).
- The most common malignancies in Lynch syndrome are colorectal carcinoma and gynecological cancers, endometrial carcinoma being the most common among gynecological malignancies followed by ovarian carcinoma.
- Other malignancies that have been observed in lynch syndrome are gastric cancer, small bowel malignancies, hepatobiliary epithelial carcinoma, uroepithelial epithelial carcinoma and brain tumors.

## Li-Fraumeni Syndrome
- Li-Fraumeni Syndrome is an autosomal dominant disorder caused by germline mutation in TP53, the most mutated gene in human cancers. The most common of the mutations are missense mutations.
- TP53 encodes for a transcription factor that responds to various cell signals and is a major regulator of the cell cycle. It is involved in variety of cellular functions such as cellular proliferation and cell cycle, apoptosis, and stability & integrity of the genome.
- Mutations in TP53 resulting defective or decreased p53 are not only implicated in pathogenesis but also impact prognosis, causing worse survival rate among the individuals with the mutations.
- These mutations are most commonly observed in epithelial ovarian cancer (47%), colorectal carcinoma (43%), head/neck cancer (42%), and esophageal cancer (41%). Breast cancer, sarcoma and brain, and adrenocortical carcinoma account for majority of the tumors encountered in Li-Fraumeni syndrome.

## Site-Specific Ovarian Cancer
- A term used to describe families in which there are several relatives with epithelial ovarian cancer but no other co-existent malignancies that are associated with other hereditary syndromes associated with epithelial ovarian cancer.
- A hypothesis is that it is caused by gen/genes that are yet to be identified. Site-specific ovarian cancer appears to be transmitted in autosomal-dominant fashion in some families but some studies have suggested the risk to be as low as 5%.

## Cowden syndrome
- An autosomal-dominant syndrome , caused by mutations in PTEN gene, has been associated with a variety of neoplastic/non-neoplastic lesions and clinical manifestations throughout the body including:
Epithelial ovarian cancer
Hamartomatous lesions of skin and organs
Macrocephaly
Breast cancer
Thyroid cancer
Endometrial cancer
- Epithelial ovarian cancer
- Hamartomatous lesions of skin and organs
- Macrocephaly
- Breast cancer
- Thyroid cancer
- Endometrial cancer

## RAD51
- RAD51 is a recombinase that binds with eight BRC repeats of BRCA2. This allows RAD51 to be recruited to double stranded DNA breaks, an essential step in homologous recombination double stranded DNA repair.
- Some studies have suggested risk for developing ovarian cancer in RAD51 mutations is as high as six-fold. There is also an increased risk for developing breast cancer.

## PALB2
- Partner and localizer of BRCA2 (PALB2) physically connects BRCA1 and BRCA2 through N-terminal coiled-coil domain and the C terminus. This BRCA2 interacting protein plays an essential role in DNA repair.
- The association of PALB2 with ovarian cancer has not be fully established but an increased risk for breast cancer, pancreatic cancer and ovarian cancer has been observed in some studies.

## CHEK2
- CHEK2 gene encodes for a protein called checkpoint kinase 2 (CHK2). It interacts with other regulators and tumor suppressors such as TP53 to play a role in tumor suppression through cell-cycle regulation and apoptosis.
- There are conflicting results regarding association of CHEK2 with ovarian cancers. Some studies have suggested no association but the limitations were observed because of focus on only certain allelic mutations in CHEK2.

## Mre11 Complex
- Mre11 Complex is involved in DNA repair and comprises of meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin).
- This complex plays an essential role in homologous recombination mediated DNA repair, non-homologous end-joining (NHEJ) and alternative non-homologous end-joining (A-NHEJ) pathways, all involved in double stranded DNA repair.
- Some studies have suggested an increased susceptibility to ovarian and breast cancers in hereditary mutations in Mre11 complex.

## BARD1
- This gene encodes for a peptide that interacts with BRCA1 and forms a heterodiamer that plays a role in homologous recombination mediated repair of double stranded DNA breaks.
- Mutations in BARD1 have been associated with breast and ovarian cancer.

## BRIP1
- BRCA1-interacting protein 1 (BRIP1) encodes for a helicase that interacts with BRCA1 in homologous recombination mediated repair of double stranded DNA breaks.
- Mutation in BRIP1 gene association with familial ovarian cancer have been demonstrated in some studies. There also been proposed risk for breast cancer but it has yet to be established.