domingo, 23 de noviembre de 2014

Screening an Asymptomatic Person for Genetic Risk — NEJM

Screening an Asymptomatic Person for Genetic Risk — NEJM


Screening an Asymptomatic Person for Genetic Risk

N Engl J Med 2014; 370:2442-2445June 19, 2014DOI: 10.1056/NEJMclde1311959
 Comments and Poll open through July 2, 2014
Citing Articles (3)


Jim Mathis is a 45-year-old health-conscious man who has been a patient in an internal medicine–primary care practice for several years. At today's visit, he talks about the family tree that he has sketched out and his discovery that three of his relatives had cancer — one had breast cancer, one ovarian cancer, and one prostate cancer.
Normally, Mr. Mathis is not an anxious patient, but he does pay close attention to his health. He exercises regularly and runs in half-marathons with his wife during family weekends. He pays attention to his diet, understands many medical terms, and knows the results of his most recent laboratory tests. He sees his physician twice a year for a physical examination and for adjustment of his medication for exercised-induced asthma. The medications include an inhaler before exercise and an oral prophylactic medication. He has no allergies. He was admitted to the hospital once last year for an exacerbation of asthma. In the past, the only conditions he has mentioned in his family history are hypertension and stroke.
During the visit today, his family history is reviewed. Mr. Mathis tells you that the family tree was constructed at a genealogy workshop that he attended after visiting cousins in Europe. During a discussion of the family tree with his 70-year-old mother, he learned that his aunt had died of breast cancer when she was 52 years of age and that his uncle had had fatal prostate cancer. Another female relative had had ovarian cancer, but his mother couldn't recall which relative had that cancer or what the outcome was. He says that he has read about whole-genome sequencing, which he defines as the determination of the DNA sequence of all a person's genetic material.
He asks about genetic testing and about any preventive measures he can take “before the cancer gets me.” You tell Mr. Mathis that genetic screening can be performed to identify genetic susceptibility to cancer, with the use of panels of cancer genes, or to identify genetic susceptibility to genetic diseases as well as cancer, which would involve whole-genome sequencing.


Do you think that Mr. Mathis should undergo genetic screening? If so, should he be referred for whole-genome sequencing or sequencing of cancer genes only? Which of the following options would you recommend for him?
1. Recommend sequencing of cancer genes only, if certain conditions are met.
2. Recommend whole-genome sequencing.
To aid in your decision, two experts in the field defend these approaches in the essays below. On the basis of your reading of published literature and other information sources, your clinical experience, your knowledge of the patient's history, and your assessment of the experts' opinions, which option would you chose? Make your choice and offer your comments at


Exon: The portion of a gene that encodes amino acids.
Gene panel: A gene panel is designed to evaluate coding and certain noncoding parts of genes that, when mutated, are known to cause a specific disease or confer a risk for that disease. Cancer gene panels typically include more than 100 genes, including oncogenes and tumor-suppressor genes (mutations in which can confer susceptibility to a heritable cancer syndrome). Gene panels can also be used to evaluate tumor tissue for prognostic or therapeutic uses.
Intron: The portion of a gene that is transcribed to messenger RNA (mRNA) but then removed (spliced out) before translation of the mRNA to a protein. Introns may contain regulatory information that is critical to appropriate gene expression, and intron mutations can be pathogenic.
Variant: A difference in a DNA sequence as compared with the normal reference. A variant may be benign (sometimes referred to as a polymorphism) or pathogenic (sometimes referred to as a mutation).
Whole-exome sequencing: Sequencing of the coding regions, or exons, of an entire genome.
Whole-genome sequencing: DNA sequencing that targets the entire genome, even though coverage is not 100%; sometimes termed genome shotgun sequencing. Whole-genome sequencing provides the sequence of coding regions of DNA (exons) as well as noncoding regions of the genome, including introns and intergenic regions.
  • Treatment Option 1: Recommend Sequencing of Cancer Genes Only, if Certain Conditions Are Met
  • Treatment Option 2: Recommend Whole-Genome Sequencing
Treatment Option 1 (74)
Treatment Option 2
Recommend Sequencing of Cancer Genes Only, if Certain Conditions Are Met
Wylie Burke, M.D., Ph.D.
Mr. Mathis's family history of cancer could indicate inherited risk, and genetic testing might help to define his risk. However, more information is needed before testing is performed. Furthermore, if testing is pursued, a whole-genome analysis is not the best approach, nor is this patient the right person to test.
The first step in the decision-making process is obtaining a detailed family history. Were all the relatives with cancer biologically related to the patient? If so, this family history may indicate the hereditary breast–ovarian cancer syndrome, a genetic predisposition caused by mutations in the BRCA1 and BRCA2 genes, leading to an increased risk of breast cancer (in both women and men), ovarian cancer, and, to a lesser degree, prostate cancer.1 Some other genes are associated with an increased risk of breast or ovarian cancer, and although most are either rarer than BRCA1/2 or associated primarily with other cancers, they should, nevertheless, be considered. Genes associated primarily with the risk of prostate cancer are also known, but their use in guiding care has not been established.
Before testing, it is also important to confirm that all the affected relatives are in the same biologic line. For example, if the aunt with breast cancer was the mother's sister and the aunt with ovarian cancer was the father's sister, their cancers are probably unrelated, and concern about inherited risk would be reduced. If the affected relatives are in the same biologic line, a cancer history should be obtained for other relatives in that line. Genetic counseling can help this evaluation and guide family members through their testing options.2 Living relatives with a history of cancer are most likely to have informative genetic testing results. A review of the family history may also suggest other inherited cancer syndromes. For example, a family history of early-onset brain tumors or osteosarcomas would suggest the Li–Fraumeni syndrome, an inherited cancer syndrome accounting for a small percentage of inherited breast cancers.3
The second step in the decision-making process is identifying the person to be tested. A living biologic relative who has breast or ovarian cancer (for example, a daughter of one of the deceased aunts) would be the best person to test. If the test is positive, identifying a genetic mutation associated with cancer risk, other family members can be tested to determine whether they have inherited that risk. If the test result is normal, there are two possible explanations — either a genetic risk is not, in fact, present in the family or the particular genetic risk in the family has not yet been defined and is therefore not discoverable by testing. In either of these cases, testing of unaffected family members would be uninformative. In the case presented here, if no affected relative is available for testing, the next best person would be Mr. Mathis's mother (assuming that all the affected relatives are on her side of the family) because she is more likely than Mr. Mathis to have inherited the familial risk. If a cancer-predisposing mutation is found, it will inform her health care, and Mr. Mathis can then be tested for it to assess his own risk.
The third step in the decision-making process is determining the best test to perform. Whole-genome sequencing generates a host of extraneous results, some potentially confusing or distracting, and is more costly to interpret. In keeping with the principle of focusing testing on the clinical question, the best testing approaches would either use a targeted gene sequencing panel, testing comprehensively for mutations in genes known to be associated with inherited breast and prostate cancer risk, or start with BRCA1/2 testing and proceed to more comprehensive testing if the results are normal.
Disclosure forms provided by the author are available with the full text of this article at


From the Department of Bioethics and Humanities, University of Washington, Seattle.

74 Reader's Comments

July 02, 2014

Whole Genome Sequencing test

I think that a whole genomic test should be performed to his mother, and if a genetic alteration is found search that genetic alteration in the patient. Considerations should be made about costs, performance (25%) and interpretation of the test. In addition, consideration about the patient and family concern related to the information that may provide the test.
ALLAN HARRIS | Physician - FAMILY MEDICINE | Disclosure: None
Gloucester United Kingdom
July 01, 2014

Are you a "Type A" or a "Type B" ?

Speaking as a type B person, my natural tendency would be along the lines of, well, ignorance is bliss. I think that a health-driven culture may well push people into a wide variety of genetic testing, leaving them with a bewildering set of results which would then drive health behaviours that may well lead to a good deal of unhappiness and discord. The arrival of genetic testing coupled with the internet is a powerful catalyst for the worried well to put pressure on their family physicians to authorise testing. Genetic testing has to be seen in context and not as the holy grail. I have a number of patients who know they have the genes for specific illnesses but as yet are asymptomatic. Whilst this does allow for advanced planning, it also casts a long shadow over their lives and those of their families.
ZHIFEI ZHANG | Student | Disclosure: None
June 30, 2014

Give the patient what he needs based on what we know

Since the patient is so conscious about his health and intend to find out any potential risk to cancer due to his family history, the first thing to do would be palliate the patient from any kind of potential anxiety. Next, before we jump to conclusion, a much-more detailed family history should be attained ( Are all the relatives biologically related to the patient? Are they from the same side of the family? The age of cancer onset? etc.). The patient wants answer, we should better give him some with a right and cost-effective approach. Whole genome sequencing would be too much in both cost and interpretation and could sometimes cause confusion. Specific cancer gene screening based on family history would be the best approach right now (BRCA1/2 gene etc).
MIKEL GOODWIN | Other | Disclosure: None
June 30, 2014

Educate, Recommend, but final decision is Patient's

Great comments from multiple practitioners; many of those comments are complementary despite differing perspectives and differing recommendations. Although my assumptions could be wrong, patient seems very engaged, takes responsibility for own health, and is well-educated in a general sense. Therefore, pt probably is able and willing to absorb extensive information about the potentials and equally important limitations of genetic testing. Offer patient as much information (pro and con) as possible. Once patient understands potentials and limitations, he should be in good position to decide for/against testing and to what extent. Factors besides strictly medical (e.g., financial) may come into play.
ADELE SCHNEIDER, MD | Physician - CLINICAL GENETICS | Disclosure: None
June 27, 2014

No testing before genetic counseling

This history should not be ignored! The best way to learn if he is a candidate for genetic testing is to meet with a genetic counselor trained in cancer genetics. This meeting would provide him an opportunity to have the genetic counselor draw his family tree and ask relevant questions that might uncover more information that the patient has not thought of. The genetic counselor will also try to obtain records to confirm the cancer diagnoses. The patient will learn the risks, benefits, costs etc of different types of genetic testing, what insurance will cover and he will then make an educated decision about the testing that is recommended after a thorough genetics review of his family and his healthy history. It may be suggested to test one of the relatives who has had cancer if they are still alive. A negative test in this patient is not a true negative unless you know that there was a positive test in his family. So testing him alone may have limited utility. There are now insurance companies who will not pay for genetic testing for cancer genes unless the patient has had genetic counseling. An educated patient is one who has had genetic counseling.
Irene M van Langen | Physician - Genetics | Disclosure: None
June 27, 2014

Who are we to judge?

Which technique is most appropriate to answer the question depends on performances and costs and the trade off between advantages and harms. One of the advantages or risks, depending on the viewpoints of those involved, could be the finding of pathogenic mutations not related to the diagnostic question at hand. If such mutations are known to be associated to diseases with preventive options (like CVD), this clearly would be advantageous information for the counselee and his relatives, provided that he consciously consented. Since we consider the analysis of ‘actionable’ genes - not related to the initial medical indication - to be screening rather than diagnostic testing, the health care-system should, in our view, not yet be burdened with its costs, even in a rich country like ours. But, if patients are willing to pay for this screening and counseling themselves, who are we to judge this negatively? If costs of sequencing, including the interpretation efforts and number of unclassifiable variants, continue to decrease, WGS rather than gene panels or WES may indeed become the optimal technique. We (Dpt Genetics, UMCG, The Netherlands) expect this will still take some years.
ALKA EKBOTE | Student | Disclosure: None
June 25, 2014

Too many presumptions!

The way to approach hereditary Breast and ovarian cancer is the detail in the family history.Best will to get the details of the family history on both side of the family atleast down to three generation. I would also like to know the type of cancers they had and at what age they were diagnosed. The risk to the immediate family of Uncle and aunt also would decide how much of these cancers transmitted to their family or any screening programmes were advised to them. I would like to know if his mother is undergoing any screening programme or advised any such. The genes for the sporadic and hereditary cancers are different and but most of the cancer causing genes are penetrant. The environment plays an important role.Having a mutation does not amount to cancer and vice versa.Predictions can lead to anxiety. If Mr Mathis mother is asymptomatic and has no cancer at present. There is no need for any genetic screening.In the case of acquired cancers the mutations are gained throughout the life and any one time one can get the cancer. Lifestyle change, good exercise and periodic and regular health checkup can be the best answer for him.
MICHIHARU IKAWA | Other | Disclosure: None
June 25, 2014

Somatic mutation and genetic mutation

BRCA is popular because of Angenila Jolli. The strong corellation between the gene and the breast cancer support the decision. The study of the removal of breast is already reported in this journal. APC and NF have the certain signs of other genes. The p53 mutation will be somatic mutation.The early detection of cancer is also very diffficult on the base of screening. The removal of organ may be the ultimate selection to avoid the death from cancer completely. The .to the DNA or the recombinat error may happen at any moment of cell divisition. PET and endoscopy ( colon) have some meaning to prevent the cancer death At this moment, these method may be recommended.
BELL VILLE Argentina
June 25, 2014

I'm not sure if he really needs that test

First I usually don`t think that a patient is in a high risk of anything with an uncle or aunt ill . For me first relatives are your parents ,brothers ,sisters ,children . So, May be in this case is only necesary to reasure the patient about his mother age without any cancer (assuming that she is talking about her family) Second . Some tiimes doctors have to do what patient want to do . So ,in this case if if an affected relative is available I will suggest first a cancer panel, but if an affected relative is not available, I will suggest a whole genome test (if he can afford it .After Angelina Jolie surgery , patients comes to me asking for this test , but a US$ 2000 for the test , made them abandon their desire (unnecessary in most of them)
DORIS ZALLEN, PHD | Other | Disclosure: None
June 25, 2014

Genetic Tests are  Different

Genetic tests are different from other types of medical tests not only because in many cases, such as the one presented here, they provide only probabilistic information but for other reasons as well. For example, genes are shared in families. The information can be helpful in some families (as in alerting children to their possible disease susceptibilities), but can cause concern and strife in others (when anxiety, blame, and sibling guilt become factors). There are also potential consequences when this information becomes known to others, such as insurance companies. Given all this complexity, people must have access to genetic professionals and to educational tools that can help them decide carefully whether any genetic test under consideration fits with their values, family situations, and concerns about the future.
Bozidar Belanovic | Student | Disclosure: None
June 25, 2014

Whole genome sequencing if possible

I would suggest a whole genome sequencing if possible financially. In the past couple of years,genetics as a science has made incredible progress and it's just a start. If the prices of these genetic tests are affordable,which they are becoming,I would suggest the whole genome sequencing. As the explanation said,it could give relevant information about the cancer risk,about other hereditary diseases or risks,or about future treatment with 5-fluorouracil,and it's not that invasive or expensive. To be honest,could any money given in the cause of your own health ever be labeled as 'thrown' or 'unnecessary'? I would advise treatment option 2,because it would be really useful to find out if there is a risk for cancer,or even beter,relieve the patient of any doubt.
DARIUS LAMBERT, MD | Physician - FAMILY MEDICINE | Disclosure: None
June 25, 2014

Genetics versus Epigenetics

If you believe the expression of genes is the adaptive cellular response to many exogenous and endogenous factors, it may be very difficult to accept the theory of genetic determinism. The latter seems to be a very convenient tool for making many excuses and washing away our hands from the responsibility of maintaining the environment in a life-friendly condition, which has been contrary to the interest of the richest corporations on Earth who have the strongest lobbing in Washington and European Commonwealth (check up the petrochemical pollutions). We are not responsible for a degradation of the environment, we may justify a very expensive genetic testing, etc. In the accordance with this theory, our diseases are predetermined by our genes and there is nothing we can do; very convenient but completely irresponsible. This is not what I expect from an empathetic homo sapiens. What is the percentage of women positive for BRCA, who have cancer?. You know the answer. The BRCA may be a predisposition for developing cancer, but we know that many different factors have to occur at the same time in order to make our cells run the cancerous genetic expression for survival.
June 25, 2014

Genetic testing = half-marathon

Genetic testing in an individual who has no solid evidence of any hereditary disease? What to do next? Preventive surgery? Or psychological follow-up? And the possible errors inherent in laboratory testing? Genetic testing is also a half-marathon. It is good but not enough. We have to wait some more time to genetic screening of multifactorial diseases complete the 42,195 km.
June 25, 2014

Once these test rsults are out there; they are out there.

Most readers are not aware that genetic tests are not considered protected health information when it comes to Life Insurance and Long Term Care insurance. Genetic testing should only be done when important and immediate clinical decisions depend on it. For example the BRACA gene in a person with breast cancer.
Sirous Zeinali | Other | Disclosure: None
Iran, Islamic Republic of
June 25, 2014

No test is needed

Since only the aunt had breast cancer and the role of BRCA1 or BRCA2 in prostate cancer is not high and also the last person's relation is not confirmed. Besides men are in lesser danger for developing breast cancer, even if they are carrier of deleterious mutation. I do not recommend him to take the test unless he insists.
GAUTAM DE, MD | Physician - PEDIATRICS | Disclosure: None
June 25, 2014

Advancement of Medicine

as the science progressed to genetic level the expectations of mankind has soared high but of course few queries and doubts to be dispelled . who should be tested what should be tested when should be tested what is the affordability how does it help -prevention, cure, or otherwise what is the availability in the index case the testing of mother who is now at 70 may help her son and it may not as may help his mother by way by way of planning ,programming and by way of life style changes etc .every life of mankind runs thro planning programming and execution with some informed decisions and experiences deciphered . what i mean early intervention by way of informed decisions if any available for the index case the test for cancer genes may be of help and what we need is to be very precise .
ISABELLE THOMAS, MD | Physician - DERMATOLOGY | Disclosure: None
PARIS France
June 25, 2014

genetic vs environmental

Genetic predisposition is one thing, but it only means a particular susceptibility to a problem. I think we take the problem the wrong way. It would be so much more important to stop environmental and other causes of hormonal induced cancers than to do genetic screening, which does not prevent in any way these cancers, and gives false hopes to our patients.
Shuvashis Gupta, MBBS | Physician - Internal Medicine | Disclosure: None
Moulvibazar Bangladesh
June 24, 2014

Benefits Vs Expenses

In this scenario Mr. Mathis is concerned of cancer what is not yet documented amongst his first degree relatives. On the other hand he is leading a healthy life. In a third world country it is not a matter to give attention when huge problems are knocking every moment. On contrary, considering his affordability he may go for specific genome sequencing for cancer genes if his cancer diseased relative shows any evidence of defective gene. In addition I want to mention what will be the benefit if defective gene is detected, it will neither be treated nor create a stress on him.
Will Wiggins | Student | Disclosure: None
June 24, 2014

Peace of Mind? Or my obsession with knowing?

From the time I started reading the article, I figured genetic testing was probably unnecessary, mainly because not much can be done if it is found that there is a risk of these cancers, but my curiosity always gets the better of me, so I chose the most useful option. I assume knowing would calm the patient down as well, no?
June 24, 2014

Treatment Option 1

Treatment Option 1
Francois Maltais | Physician - Pulmonary Medicine | Disclosure: None
June 24, 2014

Healthy lifestyle, the best approach

I would not recommend genetic screening because it would not affect my recommendations or treatment. My best recommendation is to adopt healthy lifestyle including smoking abstinence, healthy diet and regular exercise.
DAVID TILLER, MD | Physician - NEPHROLOGY | Disclosure: None
June 24, 2014

Good history limited testing to satisfy the patient.

The critical issue at the begining of the discussion with the patient will be to obtain a full family history and determine the relationships between the patient and those with cancer. If it appears that there are first degree relatives with breast,prostate,other malignancy then tageted testin may help the patient understand where this process is.
Frank Cardenas | Physician - Surgery, General | Disclosure: None
June 24, 2014

Genetic test will come.

Genetic test is a new tool in modern Medicine. It needs to be done by specialized professional people preferible MDs. Otherwise it could be dangerous. Frank Cardenas
STEPHANIE GREENBERG, RN CDE | Student | Disclosure: None
June 24, 2014

Inexpensive Genetic testing

As a masters trained nurse and a 25 year survivor of stage 3 breast cancer survivor I would have welcomed genetic testing before my diagnosis and treatment. I had it done many years later and was positive for a variation of BRCA 1. At that time it cost me $3600 out of pocket (my insurance wouldn't cover it labeling it "Experimental" at that time, although now routinely done for breast cancer survivors with coverage. Now with companies such 23 & Me a genetic profile can be done for only $99. Yes it still likely be uncovered in the scenario presented.but the costs have come way down and have made it affordable for most. Many individuals would be happy to shell out this amount to know their risks. I could change decision making, future planning and enact lifestyle changes. There are disease such as Alzheimer's that I've heard many arguments about, most frequently,"What is the use of knowing if you can't do anything about it". I for one would welcome the information as a way plan for my future, share with my family and healthcare providers and express my wants and needs. Ignorance is not always bliss.
June 24, 2014

Screening is no Treatment!  

Screening is no Treatment! On the contrary. What might be the treatment? Prostatectomy? What can be done if the tests are positive for cancer genes?

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