1. NGS panel - Genetic testing for ovarian cancer

Ovarian cancer

May 07, 2018

Disease summary:

Amongst gynecological cancers, ovarian cancer is the most common cause of death in women. Familial ovarian cancer is a complex condition and one of the most common malignancies worldwide, that can be classified in several histological subtypes, characterized by specific cells of origin, clinical features, molecular compositions and treatment responses 1, 2. As 20% (1 in 5) of ovarian cancer cases are due to an inherited pathogenic variant in a cancer predisposition gene, genetic counseling and testing is recommended for every woman diagnosed with ovarian cancer. 

Autosomal dominant 

  • The number of new cases of ovarian cancer is 12.1 per 100,000 women per year 1, 3.
  • The lifetime risk of developing ovarian cancer is about 1 in 70.
  • About 1/5th of ovarian cancer cases are due to a hereditary condition.4

Major clinical symptoms 3:

Early stage ovarian cancer:

  • Pain in the lower abdomen or side
  • A feeling of fullness in the abdomen.

Later stage ovarian cancer:

  • Back, abdominal pain
  • Irregular periods
  • Increased passing of urine
  • Constipation
  • Swollen abdomen

Advanced stage ovarian cancer:

  • Constipation
  • Tiredness
  • Loss of appetite
  • Shortness of breath

Hereditary ovarian cancer should be suspected in individuals who are fulfilling one or more of the following criteria, according to the National Comprehensive Cancer Network Guidelines 16:

  • Ovarian cancer at any age
  • Family history of ovarian cancer at any age
  • Breast cancer diagnosed at or before age 50 years
  • Multiple primary breast cancers, male breast cancer or triple-negative breast cancer, particularly when diagnosed before age 60 years
  • The combination of pancreatic cancer and/or prostate cancer with breast cancer, and/or ovarian cancer
  • Breast/ovarian cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
  • Two or more relatives with breast/ovarian cancer, one under age 50 years
  • Three or more relatives with breast/ovarian cancer at any age
  • A previously identified BRCA1 or BRCA2 pathogenic variant in the family
  • Identification of a heterozygous pathogenic variant in one of the following genes (besides BRCA1/2)(Table 1): BARD1, BRIP1, EPCAM, MLH1, MRE11A, MSH2, MSH6, NBN, PMS1, PMS2, RAD50, RAD51C, RAD51D, STK11, TP53.
  • The main treatments for ovarian cancer include risk-reducing oophorectomy, chemotherapy, hormone therapy, targeted therapy and radiation therapy.
  • Women with ovarian cancer identified to have BRCA1/2 mutations are eligible for treatment with PARP inhibitors which are FDA-approved.
  • Ovarian cysts
  • Endometriosis
  • Pelvic inflammatory disorders
  • Appendiceal, adnexal or peritoneal tumors
  • Colon, uterine or pancreatic cancer
  • Gastric adenocarcinoma
  • Ovarian torsion
  • Pelvic abscess
  • Irritable bowel syndrome
  • Ectopic pregnancy

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for ovarian cancer using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the ovarian cancer panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step 1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

Genetic testing for ovarian cancer is recommended to persons that show one or more of the following features:

  • History of breast/ovarian cancer   
  • Positive family history of the ovarian cancer e.g. when there are ovarian cancer in individual family members or multiple cases of breast cancer and/or ovarian cancer on the same side of the family.
  • Present endometriosis and/or inability for pregnancy
  • Use of birth control
  • Women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of a family history.

Confirmation of a clinical diagnosis through genetic testing of ovarian cancer can allow for genetic counseling and may direct medical management.

The most common genes associated with ovarian cancer are BRCA1 and BRCA2 (10%-40% of hereditary ovarian cancer cases3, 6, 7). Hereditary ovarian carcinoma risk has also been attributed to MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, PTEN, STK11 and other genes 14, 15, 3,  4, 7, 8. Germline pathogenic variants in ATM, CHK2, NBS1, RAD50, PALB2, BRIP1 and other genes also moderately increase breast cancer risk 3,  4, 7, 8, 14, 15 (Table 1). 

Table 1. Overview of genes included in CENTOGENE´s Ovarian cancer panel

chr. locus
Protein Allelic disorders
2q35 BRCA1-associated RING domain 1 Susceptibility to breast cancer (OMIM: 114480)
17q21.31 Breast cancer 1 gene Susceptibility to familial breast cancer type 1 (604370); Susceptibility to pancreatic cancer type 4 (614320)
13q13.1 BRCA2 gene Breast-ovarian cancer type 2 (612555); Fanconi anemia D1 (605724); Pancreatic cancer (613347); Prostate cancer (176807); Wilms tumor (194070); Susceptibility to Breast cancer, male (14480); Glioblastoma type 3 (613029); Medulloblastoma (155255)
17q23.2 BRCA1-interacting protein 1 Breast cancer, early-onset (114480); Fanconi anemia J (609054)
2p21 Epithelial cell adhesion molecule Colorectal cancer, hereditary nonpolyposis, type 8 (613244); Diarrhea 5, with tufting enteropathy, congenital (613217)
3p22.2 MutL homologue of E.Coli type 1 Colorectal cancer, hereditary nonpolyposis, type 2 (609310); Mismatch repair cancer syndrome (276300); Muir-Torre syndrome (158320)
11q21 Meiotic recombination 11, homolog of S. cerevisiae A Ataxia-telangiectasia-like disorder (604391)
2p21 MutS, homolog of E. Coli type 2 Colorectal cancer, hereditary nonpolyposis, type 1 (120435); Mismatch repair cancer syndrome (276300); Muir-Torre syndrome (158320)
2p16.3 MutS homolog of E. Coli type 6 Colorectal cancer, hereditary nonpolyposis, type 5 (614350); Endometrial cancer, familial (608089); Mismatch repair cancer syndrome (276300)
8q21.3 Nibrin Aplastic anemia (609135); Leukemia, acute lymphoblastic (613065); Nijmegen breakage syndrome (251260)
2q32.2 Postmeiotic segregation increased S. Cervisiae type 1 Colorectal cancer, non-polyposis (no OMIM); Breast and ovarian cancer (no OMIM)
7p22.1 Postmeiotic segregation increased S. Cervisiae type 2 Colorectal cancer, hereditary nonpolyposis, type 4 (614337); Mismatch repair cancer syndrome (276300)
5q31.1 RAD50, homolgue of S. Cervisiae 50 Nijmegen breakage syndrome-like disorder (613078)
17q22 RAD51 paralog C Fanconi anemia, complementation group O (613390); Susceptibility to breast-ovarian cancer type 3 (613399)
17q12 RAD51 paralog D Susceptibility to breast-ovarian cancer 4 (614291)
19p13.3 Serine/Threonine protein kinase 11 Melanoma, malignant, somatic (no OMIM); Pancreatic cancer (260350); Peutz-Jeghers syndrome (175200); Testicular tumor, somatic (273300)
17p13.1 Tumor protein 53 Breast cancer (114480)- Colorectal cancer (114500); Li-Fraumeni syndrome (151623); Adrenal cortical carcinoma (202300); Choroid plexus papilloma (260500); Hepatocellular carcinoma (114550); Nasopharyngeal carcinoma (607107); Osteosarcoma (259500); Pancreatic cancer (260350); Basal cell carcinoma type 7 (614740); Glioma susceptibility type 1 (137800)