By Molly A. Brewer, DVM, MD, MS

Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington

Dr. Brewer reports she receives grant/research support from the National Cancer Institute.

SYNOPSIS: Genetic testing has changed rapidly over the past three years, so to prevent cancer, it is critical that obstetricians-gynecologists take a complete family history, identify women at risk, and make appropriate referrals for genetic counseling with potential testing to prevent cancer.

SOURCE: Hall MJ, Obeid EI, Schwartz S, et al. Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome and beyond. Gynecol Oncol 2016;140:565-574.

A recent review paper outlined genetic testing for BRCA1/2, Lynch, and other recently identified genes that predispose women to gynecologic cancers.1 Over the past three years since Myriad Genetics lost its patent on gene testing for BRCA1/2 mutations, there has been an explosion of companies doing genetic testing, with eight additional companies doing panels of genes. These gene panels have expanded testing beyond BRCA1/2 mutations significantly. Genetic testing for cancer predisposition is a relatively recent phenomenon and has only been available for about 20 years. Mary Claire King and her group initially discovered BRCA1 in 1990 and cloned it in 1994, leading to the patent by the company that would later become Myriad Genetics. BRCA2 was discovered in 1996, but widespread testing for this gene mutation took another 10 years. In 2002, Myriad Genetics launched a campaign of direct-to-consumer marketing to promote BRCA 1/2 testing to all physicians. There was considerable concern about the lack of genetic counseling that accompanied this testing, because the implications of a positive test, a negative test, and an uncertain result, a variant of uncertain significance (VUS), are very different. In addition, because of Myriad’s patent, no other labs could offer commercial genetic testing until the patent was overturned in 2013. Prior to overturning the patent, the cost of open reading frame testing for BRCA1/2 was more than $4,000. With the development of next generation sequencing (Next-gen) and the revocation of the patent, the cost for multigene testing became much less than the earlier patent-protected testing.

The best known inheritable cancer syndrome is hereditary breast and ovarian cancer syndrome. First described in 1971 by Henry Lynch,2 it is an autosomal dominant genetic disorder associated with a deleterious mutation in BRCA1 or 2 genes, which function as tumor suppressor genes. These mutations are associated with a significantly increased risk of breast cancer and ovarian cancer and are characterized by early onset cancers. BRCA1/2 mutations are responsible for 10% of breast cancers and 10-20% of ovarian cancers. Risk of ovarian cancer varies with mutation, but BRCA1 carries a 44-63% lifetime risk of ovarian cancer and BRCA2 carries a 27-31% lifetime risk by age 70 years.3,4 These are extremely high compared to the baseline population risk of 1.5-1.7% lifetime risk.

Henry Lynch also described Lynch syndrome (hereditary nonpolyposis colorectal cancer). Initially, Lynch syndrome was described as an increased risk of colorectal cancer but was soon extended to endometrial and ovarian cancers.5 These cancers are due to deleterious mutations in mismatch repair genes MLH1, MSH2, MSH6 and PMS2. MLH1 and MSH2 are associated most strongly with early-onset colorectal cancer and endometrial cancer. MSH6 is associated with a higher risk of endometrial cancer.6 At least 20% of ovarian cancers are linked to a deleterious mutation in BRCA1/2 or Lynch and another 5% are due to other mutations.7,8

Genes other than BRCA1/2 associated with an increased risk of ovarian cancer include BRIP1, RAD51C, RAD51D, and MRE11. BRIP1 has been reported to have a relative risk (RR) of 11-14 for ovarian cancer and RAD51D a RR of 6.3.1 Other mutations include MRE11, NBS1, and RAD50, which all are associated with an increased risk of ovarian cancer.9

COMMENTARY

Why is it important to identify mutations associated with an increase in gynecologic cancer risk? Obstetrician-gynecologists are the optimal physicians to identify these women at risk. Family history remains the cornerstone of identifying women who should be referred for genetic counseling and testing.10 By taking a careful family history, and referring patients for genetic testing and counseling, women who are identified as carrying a deleterious mutation can undergo either an increase in screening or prophylactic surgery to avoid many of these cancers.10,11 In addition to identifying a risk of gynecologic cancers, women or their families may be at risk for other cancers, including breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, and melanoma, and they also can be referred for appropriate screening.

Should obstetrician-gynecologists test for mutations that may predispose their patients to cancer? Unfortunately, most physicians do not understand the complexity of the new mutations nor do they understand the implications of a negative test, particularly if the patient who underwent genetic testing did not have cancer. They do have the background to understand the implications of a variant that has not been classified as deleterious or benign, which is called a VUS. With the genetic information changing so rapidly over the past three years, taking a complete family history, identifying women at risk, and making appropriate referrals for genetic counseling with potential testing is critical to our role as obstetricians-gynecologists to prevent cancer.

REFERENCES

  1. Hall MJ, Obeid El, Schwartz S, et al. Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome and beyond. Gynecol Oncol 2016;140:565-574.
  2. Lynch HT, Krush AJ. Carcinoma of the breast and ovary in three families. Surg Gynecol Obstet 1971;133:644-648.
  3. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 2003;72:1117-1130.
  4. Pal T, Permuth-Wey J, Betts J, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian cancer cases. Cancer 2005;104:2807-2816.
  5. Lynch H, Krush AJ. Hereditary and adenocarcinoma of the colon. Gastroenterology 1967;53:517-527.
  6. Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: A report of 121 families with proven mutations. Clin Genet 2009;5:141-149.
  7. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011;108:18032-10837.
  8. Pennington KP, Swisher EM. Hereditary ovarian cancer: Beyond the usual suspects. Gynecol Oncol 2012;124:347-353.
  9. Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: Not only BRCA 1 and 2 genes. Biomed Res Int 2015;2015:341723. doi: 10.1155/2015/341723.
  10. Moyer VA; U.S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancers in women: US Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:271-281.
  11. Nelson HD, Fu R, Goddard K, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet]. Rockville, MD: Agency for Healthcare Research and Quality; 2013. Available at: http://www.ncbi.nlm.nih.gov/books/NBK179201/. Accessed July 25, 2016.