How Old Is Too Old for Genetic Testing? The Importance of Testing the Most Appropriate Family Member

TON - April 2012, Vol 5, No 3 published on April 30, 2012 in Genetic Counseling
Cristi Radford, MS, CGC

Sarah is a 59-year-old female referred by her OB/GYN provider for genetic counseling and cancer risk assessment. She has never had a diagnosis of cancer, colonic polyps, or benign tumors. Additionally, she has never undergone any risk-reducing surgeries, and no family members have undergone genetic testing. When making her appointment, she expresses concern about her risk of pancreatic cancer because 2 of her brothers died of it (per medical records adenocarcinoma of the pancreas). What else would you want to know? 

Background 

At least 10% of pancreatic cancer cases are estimated to be hereditary. In the absence of a gene mutation, a family with 2 or more first-degree relatives with pancreatic cancer is typically considered hereditary. For families where a germline mutation cannot be identified, the lifetime risk of pancreatic cancer depends on family history and has an increased relative risk of 1.5 to 3.4.1 The risk of pancreatic cancer increases as the number of affected family members increases. In a prospective registry-based study, members of familial pancreatic cancer kindreds with 1 affected first-degree relative had a 4.5-fold increased risk of developing pancreatic cancer, while individuals with 2 affected first-degree relatives had a 6.4-fold increased risk, and 3 or more affected first-degree relatives resulted in a 32-fold increased risk.2

Pancreatic cancer is associated with germline mutations in multiple genes, including PRSS1, SPINK1, CTRC, CFTR, CDKN2A, BRCA1, BRCA2, PALB2, STK11, MLH1, MSH2, MSH6, PMS2, APC, P53, MEN1, and VHL.3-7 Each gene has its own associated cancer risks. Thus, identifying the gene harboring the mutation is not only important for determining an individual’s risk of developing pancreatic cancer but also to provide tailored medical management for other associated cancers.

Additionally, depending on the gene mutation and/or family history, an asymptomatic individual may be able to enroll in a research study investigating pancreatic cancer surveillance modalities. Multiple professional organizations have guidelines outlining standards for the practice of cancer risk assessment. One key component is developing a genetic testing strategy that includes prioritizing the order of tests and identifying the best individual in the family to test.8,9 As pancreatic cancer is associated with numerous hereditary cancer syndromes, the clinician must develop a strategy that assesses all likely syndromes. Additionally, to provide the most accurate risk information to Sarah, the clinician should attempt, if possible, to begin testing on the most informative family member.

Family History

Sarah’s family history is imperative in developing a genetic testing strategy. In taking the family history, the genetic counselor learns: Sarah has 2 children, a daughter aged 29 and a son aged 27 years. She has 6 living siblings who all have children. Additionally, she has 3 siblings who are deceased: a sister who died of breast cancer at age 63 and 2 brothers who died of pancreatic cancer, one at age 47 and the other at age 57. Her father died at age 82 of heart disease. His family history is negative for malignancy. 

Maternal family history includes her mother, who was diagnosed with breast cancer at age 69 and died at age 73 of metastatic disease. Sarah has 2 living maternal aunts; one aunt aged 96 who was diagnosed with breast cancer at age 40. Her other living aunt, who is now in her 80s, was diagnosed with breast cancer at approximately age 60. She has 2 deceased maternal aunts.

One of these aunts was diagnosed with breast cancer at age 70 and died in her 70s, and the second aunt was diagnosed with breast cancer at approximately age 70 and also died in her 70s. She also has 1 maternal uncle who is deceased, and she does not have information about his history. Her maternal grandmother died of pancreatic cancer at age 80, and she has a great aunt who died of breast cancer in her 40s. There are at least 30 relatives, including Sarah’s multiple nieces and nephews and her maternal first cousins and their children, who are potentially at an increased risk for cancer. Sarah’s maternal family is of Irish and other non-Jewish Caucasian ancestry. Her paternal family is of English and Irish ancestry. 

Knowledge Applied to Sarah

According to the genetic counselor’s assessment, Sarah’s family is highly suggestive of a hereditary cancer syndrome and appears most consistent with a mutation in the BRCA1 or BRCA2 genes. She has multiple generations affected with cancer, early onset of cancer, and multiple cancers associated with the BRCA genes. The genetic counselor now has the option of proceeding with testing for Sarah or encouraging her to contact her maternal aunt, aged 96, who lives in Florida and is a 56-year breast cancer survivor, regarding the option of genetic testing. Testing the maternal aunt is important for 2 reasons: she is the most informative family member, and testing her is the most cost-effective method. 

In Sarah’s case, there is not currently a known familial alteration in the family. Therefore, if she tests negative for alterations in the BRCA1/2 genes, she would be considered an “uninformative negative.” Thus, she would still need to be managed as at-risk for a hereditary pancreatic syndrome, particularly BRCA1/2. Without an identified mutation in the BRCA1/2 genes in the family, it cannot be assumed that Sarah is a true negative. Additionally, the other 30+ at-risk family members would need to undergo full gene analysis of BRCA1/2 until a mutation is identified—if one is present. A true negative result would mean a mutation has been identified in the family, and Sarah does not carry it. Thus, she would be managed as general population risk. 

The genetic counselor discusses genetic testing options with Sarah. Sarah opts to speak with her aunt about genetic testing. The genetic counselor assists Sarah by locating professionals in Sarah’s geographical area familiar with cancer risk assessment. Sarah signs medical releases allowing family history information to be shared with her aunt’s genetic professional. Ultimately, Sarah’s aunt undergoes testing for the BRCA1/2 genes and is found to have a mutation in BRCA2.

Sarah’s aunt is provided with multiple copies of her family history and test results for distribution to at-risk family members, including signing releases for this information to be released directly to Sarah’s genetic provider. Armed with a positive genetic test result, the 30+ at-risk family members can now undergo single-site gene analysis for the familial BRCA2 mutation. For Sarah and other family members, this drastically changes the cost of their genetic test. Additionally, for individuals who test negative for the BRCA2 mutation, they are considered “true negatives” and most likely managed as general population risk for developing cancer.

Take-Home Messages

Testing the individual in the family most likely to have a gene mutation typically provides the most informative results and is the most cost-effective method for the family. An individual cannot be too old for genetic testing. Remember, genetic testing is relatively new. Thus, cancer survivors may not have had the option of genetic testing at the time of their diagnosis. Sometimes the most informative family member for genetic testing lives far away, such as on the opposite coast.

You can assist patients in finding professionals for cancer risk assessment by encouraging them to ask for a referral from their healthcare team. Additionally, the following Web sites may be useful: GeneTests/Clinic Directory: www.ncbi.nlm.nih.gov/sites/GeneTests/; National Society of Genetic Counselors Find a Genetic Counselor, www.nsgc.org/; NCIPDQ/Cancer Genetics Services Directory, www.cancer.gov/cancertopics/genetics/directory/.

References

  1. Haddad A, Kowdley GC, Pawlik TM, et al. Hereditary pancreatic and hepatobiliary cancers. Int J Surg Oncol. 2011. Article ID 154673.
  2. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 2004;64:2634-2638.
  3. Brand RE, Lerch MM, Rubinstein WS, et al. Advances in counseling and surveillance of patients at risk for pancreatic cancer. Gut. 2007;56:1460-1469.
  4. Hruban RH, Canto MI, Goggins M, et al. Update on familial pancreatic cancer. Adv Surg. 2010;44:293-311.
  5. Jensen RT, Berna MJ, Bingham DB, et al. Inherited pancreatic tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113(7 suppl):1807-1843.
  6. Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Arch Pathol Lab Med. 2009;133:365-374.
  7. Trepanier A, Ahrens M, McKinnon W, et al. Cancer risk assessment and counseling: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2004;13:83-114.
  8. Weitzel JN, Blazer KR, Macdonald DJ, et al. Genetics, genomics, and cancer risk assessment: state of the art and future directions in the era of personalized medicine. CA Cancer J Clin. 2011;61:327-359.
  9. Weitzel JN. Genetic cancer risk assessment. Putting it all together. Cancer. 1999;86(11 suppl):2483-2492.
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Last modified: May 21, 2015