Inherited Breast Cancer Risk: Consider the Possibilities

TON - October 2012 Vol 5 No 9 — November 19, 2012

As with most cancers, the genetic contribution to breast cancer is often classified as sporadic, familial, and hereditary. The majority of breast cancer cases, approximately 70%, are considered sporadic; these cases do not run in families and are not believed to have an underlying genetic predisposition. The remaining 30% of cases are thought to have some type of genetic influence. Traditionally, it has been estimated that 20% to 25% of cases have a “clustering” in the family, but the contribution of environment and/or genetics is unclear; these cases are considered familial.

The other 5% to 10% of cases are considered he­reditary and caused by mutations in highly penetrant breast cancer susceptibility genes. Thus, up to 30% of breast cancer cases may have an underlying inherited risk; however, the risk conveyed by the underlying gene mutation(s) may vary greatly. In 2012, this equates to approximately 68,061 newly diagnosed women1—women who also have family members, both male and female, at an elevated risk of developing cancer.

Of the cases with an inherited risk, those with germline mutations in the BRCA1/2 genes are still estimated to account for the majority of known cases (25% to 40%), while other cancer susceptibility genes account for approximately 20%, and the associated gene(s) in the remaining cases remain un­known.2,3 It is no longer believed that the majority of high-risk cases are accounted for by a “BRCA3” gene, but rather by moderate-risk breast cancer genes in a polygenic setting. Although genes other than BRCA1/2 may be individually rare, collectively they represent at least one-fifth of inherited breast cancer cases and warrant identification. Identifying individuals with an inherited risk not only allows healthcare providers to provide high-risk surveillance and risk-reducing options, it also spares individuals in a family without the familial mutation from undergoing unnecessary procedures.

DNA Repair Pathways
In simplistic terms, cancer is the un­controlled growth of abnormal cells in the body. Humans have mechanisms to prevent this from occurring, but when the DNA of a cell changes and is not repaired by these mechanisms, cell growth and division are affected. As a result, cells may not die but instead form tumors. Therefore, when a person is born with a mutation in a gene that helps repair DNA, he or she may have an increased risk of developing cancer. Thus, when searching for genes that predispose an individual to an increased cancer risk, many researchers have focused on genes involved in DNA repair pathways. One of these pathways is the Fanconi anemia (FA) pathway.

Fanconi anemia is a genetic syndrome characterized by bone marrow failure, physical anomalies, and increased risk for malignancy. Mutations in at least 13 genes cause Fanconi anemia.4 It is primarily an autosomal recessive condition. The gene products associated with the FA pathway regulate DNA repair by homologous recombination. Addition­ally, the members of the pathway interact with other proteins involved in cellular checkpoints and DNA repair. When there is DNA damage, the FA pathway sends proteins to the damaged area, triggering DNA repair. This pathway became of particular interest in breast cancer risk when it was discovered that homozygous mutations in BRCA2, a breast cancer susceptibility gene, were found to be one genetic cause of Fanconi anemia.5

Similarly, studying the Nijmegen break­age syndrome pathway led to the discovery of other genes associated with a moderate risk of breast cancer. Nijmegen breakage syndrome, also an autosomal recessive condition, is characterized by short stature, microcephaly, distinctive facial features, intellectual disability, and a variety of health problems. It is associated with homozygous or compound heterozygous mutations in the NBS1 gene, which is part of the MRE11-RAD50-NBN/NBS1 (MRN) path­way. The MRN pathway is also in­volved in DNA damage response.3 Study­ing both the FA and MRN pathways has identified several genes that place individuals at a moderately in­creased risk of developing breast cancer. Although researchers have postulated an association between genes in these pathways and the risk of breast cancer for a while, this association could not be proven without large case-control studies. Advances in genetic technology have allowed these types of studies to take place, with the result that many of the genes can now be analyzed in either a clinical or research setting through the use of “cancer panels,” a sequencing technology that can simultaneously detect mutations in multiple genes that contribute to hereditary cancers, including breast cancer.

Breast Cancer Susceptibility Genes
Genes that are known to be associated with a high risk of breast cancer include BRCA1, BRCA2, TP53, PTEN, STK11, and CDH1. These genes convey between a 10- and 20-fold increased risk for developing breast cancer.3,6,7 RAD51C and RAD51D, genes recently discovered to be linked to hereditary breast and ovarian cancer families, may also fall into this category.8 However, more studies are needed to determine if their penetrance is truly in the highest risk category. For the time being, they should be considered moderate-risk genes. Such genes place individuals at a 3- to 5-fold in­crease. Other genes in this category include NF1, CHEK2, PALB2, RAD50, BRIP1, BARD1, and MRE11.9 Additionally, ATM, NBN(NBS1), and MUTYH heterozygotes are also associated with an increased risk for breast cancer.10,11 These 3 genes are unique from the other moderate-risk genes listed in that they are most recognized for the autosomal recessive genetic syndromes with which they are associated: ATM = ataxia telangiectasia, NBN(NBS1) = Ni­jme­gen breakage syndrome, and MUTYH = MUTYH-associated polyposis (MAP). When a female is heterozygous for a mutation, she also has an increased risk for breast cancer. For women of child-bearing age, being a carrier of an NBN and/or ATM mutation also has implications for preconception and prenatal genetic counseling, as the offspring may be at risk for Nijmegen breakage syndrome and/or ataxia telangiectasia. Additionally, a recent study suggests that females with Lynch syndrome may also have up to a 4-fold risk of breast cancer.12 However, at this point, it is not clear if this is a true association and if it is true for each gene associated with Lynch syndrome. It is likely that our ideas about the specific penetrance of various genes will continue to change as more is learned about them through continued research.

The Importance of Genetic Diagnosis
Females with a family history of breast cancer are considered to be at an increased risk of the disease. However, the extent of the risk depends on the family history—the risk may vary from 1.8-fold to more than 5-fold. However, if an underlying germline mutation is identified, such as in BRCA1/2, the risk may increase to 20-fold. Identifying females at an increased risk of breast cancer is important as it allows mammogram and breast MRI to begin at a younger age, as well as the option of risk-reducing mastectomy. Addition­ally, the genes that place individuals at an increased risk for breast cancer also place them at an increased risk for other cancers—cancers that may be preventable.

For example, consider the case of Leslie, a 38-year-old female recently diagnosed with invasive breast cancer. Because she was adopted, her family history is almost entirely unknown. The only information she knows is that her biological mother was diagnosed with a “female cancer” at age 40 and died at age 42. Leslie’s personal and family history could be associated with a variety of mutations. If she were found to have a mutation in BRCA1, Leslie’s medical management would change to most likely include risk-reducing salpingo-ooph­orectomy, while if she were found to have a PTEN mutation she would undergo a hysterectomy and annual thyroid examinations. However, if she were found to have an alteration in STK11, her management would change to include surveillance and risk-reducing options for several cancers, including colon, stomach, pancreas, small intestine, and ovarian. At the same time, if she were found to have a mutation in PALB2, her management may only include research studies for early detection of pancreatic cancer. Thus, genetic diagnosis would impact her medical management options. Addition­ally, it would allow at-risk family members to be tested and screened appropriately.

Take-Home Messages

  • Many genes (at least 16) place a female at increased risk for breast cancer, as well as other cancers; consider all possibilities when as­sessing a survivor and at-risk family members.
  • Genetic technology and testing options continue to evolve; re­member to assess individuals for genetic testing options on an annual basis.
  • Although “panel testing” appears optimistic, its use in clinical care will continue to evolve as more is learned about the cancer risks conveyed by moderately penetrant genes.

References

  1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2009 (Vin­tage 2009 Populations). Bethesda, MD: Na­tion­al Cancer Institute. http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER website, April 2012.
  2. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006; 295(12):1379-1388.
  3. Hollestelle A, Wasielewski M, Martens JW, et al. Discovering moderate-risk breast cancer susceptibility genes. Curr Opin Genet Dev. 2010;20(3):268-276.
  4. D’Andrea AD. Susceptibility pathways in Fanconi’s anemia and breast cancer. N Engl J Med. 2010;362
    (20):1909-1919.
  5. Howlett NG, Taniguchi T, Olson S, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297(5581):606-609.
  6. Schrader KA, Masciari S, Boyd N, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer. 2008;7(1):73-82.
  7. Chun N, Ford JM. Genetic testing by cancer site: stomach. Cancer J. 2012;18(4):355-363.
  8. Meindl A, Hellebrand H, Wiek C, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42(5):410-414.
  9. Ripperger T, Gadzicki D, Meindl A, et al. Breast cancer susceptibility: current knowledge and implications for gen­etic counseling. Eur J Hum Genet. 2009;17:722-731.
  10. Pennington KP, Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol. 2012;124(2):347-353.
  11. Win AK, Cleary SP, Dowty JG, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer. 2011;129 (9):2256-2262.
  12. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30:958-964.

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