Genetic Susceptibility to Cancer

I love the pen. It has the ability to befuddle, convince, coerce, and give false or true hope. This is the case with journal articles. I am always amazed by what is reported and what is real. You see, the Buddhists will tell you that all reality is merely false. Why? Because perception is what we view to be reality. Since reality needs to be constant, yet perception not only changes but is viewer dependant....it is not constant. Hence, there is no spoon.

This is the case with a recent article published in JAMA's clinician's corner. The article entitled "Genetic Susceptibility to Cancer" did something wonderful. It took 161 meta and pooled analyses encompassing 18 cancer sites and 99 genes/344 variants (Trust me, this took some heavy lifting) and evaluated for Odds Ratios and evaluated statistical significance. They then evaluated the false positive report probability (this is very important when trying to decide which genes are noteworthy/FPRP) Most evaluated polymorphisms were from either metabolizing genes or DNA repair genes. Big surprise, especially given Knudson's 2 hit hypothesis. (2 mutations to cause a cancer, thus if you can process the toxin quicker than it can cause damage or if you can fix the damager quicker than it causing cancer, You Win. Or Vice Versa)

So what did they find and what did they list in their abstract?

Findings: 13 of the 344 variants had OR >1.5, Only 4 IMHO were noteworthy (OR 2.0 or FPRP<0.2)>

Reported in abstract: "....nearly one-third of gene variant cancer associations were statistically significant, with variants in genes encoding for metabolizing enzymes among the most consistent and highly significant"

See how my bolding made it seem more important? That is the problem here. All this study let me know is that most gene studies involving linkage and cancer are not significant. But the busy clinician reads this as the bold. Not that there are only 3 Linkages worth a hoot with OR of at least 1.5

Those associations ARE: NAT2 slow acetylator and bladder cancer, MTHFR C677T and gastric cancer, lastly GSTM1 null allele and bladder cancer. This makes sense, especially given the fact that these cancers have been linked to environmental exposures....

The Sherpa Says:

Abstracts are misleading. To fully report on these articles one must really read the article. How does the busy clinician or journalist have time for that? The Sherpa is even finding it hard! As for Senator Kennedy, that cancer is likely genetic. IMHO

Senator Kennedy's Cancer Family History

Dr Lubin, my partner at Helix Health of Connecticut asked me this question.

"Am I the only one to think about this? Ted Kennedy Junior had Osteosarcoma. His other son Patrick had a Spinal Tumor (I'd love to see the path on that). Ted Senior has a Glioma.....Likely GBM. In addition, his daughter had lung cancer at 43 (Was she a smoker?) and breast. So what this tells me is that the Kennedy family may have Li-Fraumeni or Li Fraumeni Like."

Well, perhaps we should call Dana Farber. Why? Because, Dr Rosenthal over there does not seem to be impressed. from the Globe:

Dr. David S. Rosenthal, former president of the American Cancer Society and the medical director of the Leonard P. Zakim Center for Integrated Therapies at the Dana-Farber Cancer Institute, said that while he is not familiar with the details of the Kennedys' medical history, he considers it "unlikely that the cancers are related." Given the young age at which some of the Kennedys' cancers occurred, and the fact that they were found in different organs, it is unlikely, but not impossible, that there is a common genetic thread linking them.

Hmm, let's see what a little GeneTests search can do. BTW the article was written by a Dana Farber genetic counselor.

Disease characteristics. Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. Individuals with LFS are at increased risk for developing multiple primary cancers.

Hmmmm....

Genetic counseling. LFS is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the disease-causing mutation. Predisposition testing for at-risk family members is available in families in which the disease-causing mutation has been identified.

Two forms of Li-Fraumeni syndrome are recognized: classic Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL).
Classic LFS is defined by the following criteria:

A proband with a sarcoma diagnosed before 45 years of age AND

A first-degree relative with any cancer under 45 years of age AND

A first- or second-degree relative with any cancer under 45 years of age or a sarcoma at any age [Li & Fraumeni 1969].

LFL shares some, but not all of the features listed for LFS.

Warmer.....

Birch's definition of LFL [Birch et al 1994]:

A proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age (Ted Junior) AND

A first- or second-degree relative with a typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, or leukemia) at any age (Ted Sr) AND

A first- or second-degree relative with any cancer under the age of 60 years (Daughter age 43)

Well Harvard. Looks like you were scooped by Helix Health of Connecticut.......

To the Kennedys, feel free to call for a full evaluation with Dr Murray up there, if someone at Harvard hasn't had the sense to send you already!