Background:
A woman’s lifetime risk of developing breast cancer is approximately 12%. Furthermore, a woman’s lifetime risk of developing ovarian cancer and uterine cancer is 1.3% and 2.7%, respectively. Most cases of breast and gynecological cancers develop sporadically; however, an estimated 5-10% of cases are due to a hereditary predisposition. Although most inherited cancer predisposition syndromes are inherited in an autosomal dominant fashion, some genes on this panel are associated with clinically distinct autosomal recessive conditions.
This test analyzes 19 well-established genes associated with an increased lifetime risk of hereditary breast and gynecological (ovarian, uterine, fallopian tube, and peritoneal) cancer. Notably, the genes analyzed on this panel are associated with conditions that have published management guidelines and adherence to these guidelines may result in risk-reduction and early diagnosis, which can increase the chance of successful treatment and survival.
Factors that may be associated with hereditary breast and gynecological cancer predisposition syndromes include: early-onset of breast, uterine, endometrial, colon, pancreatic, melanoma, sarcoma, or prostate cancer, male breast cancer, ovarian or fallopian tube cancer, multiple primary cancers in one individual, and multiple affected family members.
Understanding the molecular etiology of such cancer incidence can help guide treatment and proper surveillance. Our next-generation sequencing test is designed to detect mutations in the coding regions of 19 genes associated with inherited breast and gynecological cancer predisposition syndromes. Our microarray test is designed to identify single-exon deletions and duplications in the same 19 inherited breast and gynecological cancer-associated genes. Combining deletion/duplication data analyzed by microarray with next-generation sequencing data will allow KDL to improve diagnostic yield and deliver more comprehensive results.
The results from genetic tests can facilitate assessment of levels of risk for patients and lead to more efficient and appropriate medical management. It is recommended that this testing be accompanied by a complete family history and genetic counseling.
Reasons for Referral:
- Molecular confirmation of a clinical diagnosis of inherited breast and gynecological cancer.
- To aid in decision-making for treatment and management of individuals with inherited breast and gynecological cancer.
- Testing for individuals with a positive family history for inherited breast and gynecological cancer (targeted testing is available if familial mutation is known).
Methodology:
Next generation sequencing will analyze the exons or coding regions of 19 Inherited Breast/Gyn Cancer-associated genes using Illumina NextSeq 500/550 technology. Samples are prepared using hybridization probes to enrich exonic regions.
This assay does not assess regions of insufficient coverage, introns and promoter regions; pseudogenes; where the reference genome is inaccurate or contains gaps and insertions; and regions of high GC or polynucleotide repeats, but may contain variants that impact gene function. Promoter, intronic, etc. regions are not assessed on our assay, but may contain variants that impact gene function.
Exon-level deletion/duplication analysis is performed by running the NGS data through the Genome Analysis Toolkit (GATK) Germline Copy Number Variation best practices pipeline from GATK, version 4.1.4.1. A Bayesian model was validated clinically in our lab. The model can detect copy changes at a resolution of three (3) or more probe targets (exons) for deletions and duplications in genes that do not have pseudogenes, and is not designed to detect low-level mosaicism or balanced alterations.
The 19 Inherited Breast/Gyn Cancer-associated genes are listed below:
ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53
Specimen Requirements:
Blood: EDTA or ACD (Solution A or B):
Adult: 5 mL
Child: 5 mL
Infant: 2-3 mL
Saliva: 2 ORAgene™ Saliva Collection Kit(s) (OGR-500) used according to manufacturer instructions. Please contact KDL Client Services for a Saliva Collection Kit for patients that cannot provide a blood sample.
Assisted Saliva: 4 ORAgene™ Assisted Saliva Collection Kits (OGR-575) used according to manufacturer instructions. Please contact KDL Client Services for an Assisted Saliva Collection Kit for patients that cannot provide a blood sample.
Skin Fibroblast: Punch Biopsy (Cell cultures will be prepared at KDL and used for testing), or 2 T-25 confluent flasks.
DNA: 10µg at a minimum of 60-100ng/µL (DNA must be extracted in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or CMS).
For routine testing of blood, saliva and buccal swabs, KDL does NOT accept samples from patients within two (2) weeks of a packed cell/platelet transfusion or within four (4) weeks of a whole blood transfusion. For extraordinary circumstances, where testing must be performed outside of the above windows, please contact our lab.
A REQUISITION FORM MUST ACCOMPANY ALL SAMPLES. Please include detailed clinical information, including ethnicity, clinical history, and family history.
Test Performed (Days):
Weekly
Turn Around Time:
3 weeks
Shipment Sensitivity Requirements:
- Package and ship specimen to remain cold, but not frozen.
- Ship via overnight express, using the FedEx priority overnight label provided.
- Contact Client Services for shipping kits and instructions at (855) 535- 1522.
References:
- Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated 2016 Dec 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1247/.
- Zhang B, Beeghly-Fadiel A, Long J, Zheng W. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. The Lancet Oncology. 2011;12(5):477-488. doi:10.1016/s1470-2045(11)70076-6.
Additional Info: