domingo, 6 de marzo de 2016

Genetic Screening in All Young Patients With Colorectal Cancer?

Genetic Screening in All Young Patients With Colorectal Cancer?

Genetic Screening in All Young Patients With Colorectal Cancer?

  1. Leonard B. Saltz
+Author Affiliations
  1. Memorial Sloan Kettering Cancer Center, New York, NY
  1. Corresponding author: Leonard B. Saltz, MD, Memorial Sloan Kettering Cancer Center, 300 East 66th St, Room 1049, New York, NY 10128;

To the Editor:

In their retrospective review of patients referred to the genetics service of a major cancer center over a 5-year period, Mork et al1 identified 205 patients who developed colorectal cancer (CRC) at age 35 years or younger. They conclude from their review of these individuals that “patients diagnosed with CRC at age 35 years or younger should receive genetic counseling regardless of their family history and phenotype.”1(p3544) I would respectfully suggest, however, that their data would appear to say just the opposite.
As acknowledged by Mork et al1 it is already standard practice to screen all patients in this age range for Lynch syndrome via either immunohistochemistry for mismatch repair deficiency or polymerase chain reaction analysis for microsatellite instability. Those patients (excepting those with MLH1 deficiency and concurrent V600E BRAF mutation) are routinely referred for further genetic evaluation. Of the 205 patients reviewed, 20 had a polyposis phenotype, and we can also agree that all such patients warrant and would routinely receive referral for genetic screening and counseling. Of the other 185, however, 45 were found to have mismatch repair deficiency and so are already in the category that would be referred for further genetic counseling under standard practice (12 had an incomplete work-up and are reported as inevaluable). Of the other 128 patients who had mismatch repair proficient nonpolyposis CRC, one with a striking personal history of multiple malignancies was diagnosed as having Li-Fraumeni syndrome, a diagnosis that was strongly suggested by the patient’s personal history of osteosarcoma, astrocytoma, and early-onset colorectal cancer. A germline p53 mutation was identified, which confirmed this clinical diagnosis. One patient had an incidental finding of a monoallelic MUTYH mutation, which is not of direct clinical significance; it had no known bearing on the early-onset development of colorectal cancer in this patient and did not warrant genetic counseling.
Of 127 young (age 35 years or younger) patients with CRC without either mismatch repair deficiency or a clearly displayed phenotypic justification for referral for genetic evaluation (polyposis, personal history of multiple malignancies, or compelling family history) who were evaluated, none were found to have a germline abnormality that either accounted for their CRC and/or led to identification of a specific mutation for use in genetic screening in first-degree relatives. These 127 patients, 69% of the 185 evaluable patients presented, constitute an a priori identifiable good risk subgroup who could have, in retrospect, been spared genetic testing.
In short, in contrast to their stated conclusion, Mork et al1 appear to have presented compelling support for not referring patients with CRC, even those who have early age of onset, for formal genetic counseling and screening unless they are found to have either mismatch repair deficiency, polyposis, or a striking personal or family history of malignancy. From a research perspective, genetic evaluation of an unselected group of patients with early-onset CRC for determination of mutation prevalence in known cancer predisposition genes, as well as for novel gene discovery, is certainly a worthy pursuit. However, for current clinical purposes, formal genetic screening of patients with CRC lacking existing clinical criteria, regardless of age, is not supported by the data presented and would appear at this time to constitute an unwarranted source of anxiety and expense for these patients. As genetic screening becomes a more frequent practice in oncology and in medicine in general, careful consideration of who not to screen will be an important component of assuring appropriate use of resources and adequate availability of genetic screening and counseling to those individuals whose conditions do warrant it.


Genetic Screening in All Young Patients With Colorectal Cancer?

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to

Leonard B. Saltz

Consulting or Advisory Role: Genentech, Eli Lilly, AbbVie, McNeil-PPC (I)
Research Funding: Taiho Pharmaceutical (Inst)


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