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Analysis And Comment Cancer genetics

Common susceptibility genes for cancer: search for the end of the rainbow

BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7550.1150 (Published 11 May 2006) Cite this as: BMJ 2006;332:1150

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Response to the article „Common susceptibility genes for cancer: search for the end of the rainbow” BMJ 2006; 332; 1150-1152 by SG Baker, J Kaprio.

Response to the article
�Common susceptibility genes for cancer: search for the end of the rainbow� BMJ
2006; 332; 1150-1152 by SG Baker, J Kaprio.


Dear Sir,


I read with
great interest this article, as the common susceptibility genes for cancer
constitute the primary focus of my research and clinical practice. Since 1992,
I have been managing the
InternationalHereditaryCancerCenter at the PomeranianMedicalUniversity in Szczecin, Poland.
Research data and clinical practice experience of the Center suggest
that the conclusions of the above article are unduly pessimistic.

  1. Cost of studies to detect
    common cancer susceptibility genes

Authors claim that these studies are expensive because they require
large sample size. In our center during the last 15 years we have been collecting
biological samples (mainly peripheral blood) and clinical data from over
135,000 cancer patients, their relatives and appropriate controls. Our costs of
collecting and maintaining what is probably the largest bio-bank in the world
are less than 1 mln EURO annually. Our studies are part of our normal research
and clinical practice work. . Obviously,
the costs in
Central
Europe
are
considerably smaller than in Western countries. Nevertheless, we can conclude
that collection of samples and data is not a limiting factor of discussed
studies. Furthermore, costs of detection and prevention studies should be
compared to the costs of clinical trials for late-stage cancer drugs, which are
orders of magnitude more expensive.


  1. Common cancer susceptibility
    genes certainly exist

We have identified several common cancer susceptibility genes,�� Studies of consecutive cases allowed us to
identify cancer susceptibility markers for 85% of breast cancers [3,500 cases
dgn <51 yrs; 2,000 cases dgn at any age; 4,000 controls, (table 1), 80% of
colorectal cancers, 72% of malignant melanomas, 38% of ovarian cancers and 28%
of prostate cancers.


For many of above markers we have been able to prove distinct clinical
phenotype � different age at diagnosis, characteristic histopathology,
predisposition to cancers of various but specific sites (1-6)

For example � CHEK2 mutations are predisposing to cancers of the breast,
thyroid, colon, kidney, prostate; NOD2 (3020insC) to cancers of the breast,
colon, lung, ovary; CHEK2 � I157T is associated with lobular sub-type and NOD2
3020insC with DCIS sub-type of breast cancers.

Our experience suggests that studies on identification of common cancer
susceptibility genes should be performed initially mainly on populations
showing high level of genetic homogeneity. This was the case for the Polish
population. In heterogenous populations achievement of the same data may require
much larger size of registries .



  1. Clinical benefits

Obviously, large prospective studies are needed in order to conclusively
prove clinical benefits accruing from diagnosing moderate / low cancer risk
genetic markers.

However, even at present, we can, and in the case of our Center we
already do, offer to our patients options resulting from identification of
cancer susceptibility.

Classical examples of options different from standard surveillance
programme which we offer in our center include � colonoscopies at age 60 yrs
for carriers of CHEK2, NOD2 or p16 changes, MRI of the breast beginning from
the age 40 yrs for carriers of CHEK2 I157T, mammographies from the age of 35
yrs for carriers of NOD2 3020insC, BRCA2 5972C/T or of p16 A148T. In such way
we detected already hundreds of premalignant lesions or early cancers.

In summary � common cancer susceptibility genes exist and by diagnosing
them we can save lives. Studies on moderate/low cancer risk genetic markers can
be performed effectively provided we use initially the well organized models
from homogenous populations.


Jan Lubi�ski, Ph.D

President

International Hereditary CancerCenter

PomeranianMedicalUniversity

Szczecin, Poland

���� www.hereditarycancer.net


REFERENCES

1.�����������
Cybulski C, Gorski B, Huzarski T, Masojc B, Mierzejewski
M, Debniak T, Teodorczyk U, Byrski T, Gronwald J, Matyjasik J, Zlowocka E,
Lenner M, Grabowska E, Nej K, Castaneda J, Medrek K, Szymanska A, Szymanska J,
Kurzawski G, Suchy J, Oszurek O, Witek A, Narod SA, Lubinski J.
CHEK2 is a multiorgan
cancer susceptibility gene.
Am J Hum Genet. 2004
Dec;75(6):1131-5. Epub 2004 Oct 18.

2.�����������
Debniak T,
Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, Gorski B, Cybulski C,
Medrek K, Mierzejewski M, Masojc B, Matyjasik J, Zlowocka E, Teodorczyk U,
Lener M, Klujszo-Grabowska E, Nej-Wolosiak K, Jaworowska E, Oszutowska D,
Szymanska A, Szymanska J, Castaneda J, van de Wetering T, Suchy J, Kurzawski G,
Oszurek O, Narod S, Lubinski J.
CDKN2A common variant and
multi-organ cancer risk-a population-based study. Int J Cancer. 2006 Jan 4.

3.�����������
Lubinski J, Huzarski T, Kurzawski
G, Suchy J, Masojc B, Mierzejewski M, Lener M, Domagala W, Chosia M, Teodorczyk
U, Medrek K, Debniak T, Z�owocka E, Gronwald J, Byrski T, Grabowska E, Nej K,
Szymanska A, Szymanska J, Matyjasik J, Cybulski C, Jakubowska A, Gorski B,
Narod SA, The 3020insC
Allele of NOD2 Predisposes to Cancers of Multiple Organs
, Her Can in
Clin Pract 2005; 3(2), 59-63.

4.�����������
Gorski B, Narod SA, Lubinski J. A common missense variant in BRCA2 predisposes to
early onset breast cancer. Breast Cancer Res. 2005 Oct 24; 7 (6): R1023-R1027.

5.�����������
Huzarski T, Cybulski C,
Domagala W, Gronwald J, Byrski T, Szwiec M, Woyke S, Narod SA, Lubinski J.
Pathology of breast cancer in women with constitutional CHEK2 mutations. Breast
Cancer Res Treat. 2005 Mar; 90 (2): 187-9.

6.�����������
Huzarski T, Lener M,
Domagala W, Gronwald J, Byrski T, Kurzawski G, Suchy J, Chosia M, Woyton J,
Ucinski M, Narod SA, Lubinski J.: The 3020insC allele of NOD2 predisposes to
early-onset breast cancer. Breast Cancer Res Treat. 2005 Jan; 89 (1): 91-3.


Table. 1.
Breast cancer risk markers; consecutive cancers; n=2012.


Gene Mutation Percentage in % RR
BRCA1 5382insC 1,70 10,0
BRCA1 C61G 1,00 10,0
BRCA1 4153delA 0,30 3,0
BRCA2 5972C/T 6,00 1,5-4,0
NBS1 657del5 0,80 5,0
NOD2 3020insC 9,00 2,0 (<_50 yrs="yrs" td="td"/>
CHEK2 1100delC 0,50 2,0
CHEK2 IVS2+1 G/A 0,50 4,0
CHEK2 I157T 7,00 1,5
p16 A148T 5,50 1,5
XPD* - 8,50 1,5
X1 - 7,00 1,5
X2 - 45,00 1,5
X3 - 37,00 1,5
X4 - 10,00 2,0
X5 - 10,00 2,0 (>60 yrs)
* -
Lys751Gln_CC/Asp3112Asn_AA

Competing interests:
None declared

Competing interests: No competing interests

25 May 2006
Jan Lubinski
Prof
International Hereditary Cancer Center, Pomeranian Medical University, ul. Polabska4, 70-115Szczecin