Skip to main content

Low-risk Genes and Multi-organ Cancer Risk in the Polish Population

There is continuing interest in identifying low-penetrance genes which are associated with increased susceptibility to common types of cancer. There are several approaches to this problem, including the use of chip-based single nucleotide polymorphism (SNP) arrays to interrogate a large number of genes simultaneously and pre-selecting candidate genes of interest. Candidate genes for cancers of a particular site may be selected because they are known to predispose to malignancies of other organs, or because they are mutated somatically in the cells from the cancer of interest. It is possible that missense variants of genes for which truncating mutations are clearly pathogenic may also be deleterious, but with reduced penetrance. In this situation the association may be overlooked unless large numbers of cancers are studied.

In our centre we performed population-based studies of common variants of three genes: a tumour-suppressor gene CDKN2A (OMIM 600160), NOD2 (OMIM 605956) involved in the chronic inflammation process, and CHEK2 (OMIM 604373) participating in the DNA damage response.

To determine whether CDKN2A common variant A148T may be associated with an increased risk of malignancies at different sites of origin we genotyped a series of 8,263 unselected cancer cases and compared the frequency of the change observed in this population to 3,000 controls in Poland. To establish the range of cancer types associated with three CHEK2 mutations (VS2+1G → A, 1100delC, and I157T) we genotyped 4,008 unselected cases of cancer and 4,000 controls in Poland. In order to define the range of cancer phenotypes associated with the NOD2 3020insC mutation we examined 2,604 unselected invasive cancers of 12 different types and 1,910 controls from Poland.

Results

We showed an association between CDKN2A common variant and increased risk of malignant melanoma (OR = 2.1), cancers of breast (under 50 y, OR = 1.5), lung (OR = 2.0) and colon (OR = 1.5) (table 1) [13].

Table 1 Association between A148T variants and selected types of cancer

We also found a positive association between common NOD2 variant and cancers of the colon (late-onset, OR = 2.2), breast (early-onset breast cancer OR = 1.9 and ductal breast cancer with an in situ component OR = 2.1) and ovary (table 2) [47].

Table 2 Association of the NOD2 3020insC mutation and selected types of cancer

Positive associations with CHEK2 protein-truncating alleles were seen for cancers of the thyroid (OR = 4.9), breast (OR = 2.2) and prostate (OR = 2.2). The missense variant I157T was associated with an increased risk of breast cancer (OR = 1.4), colon cancer (OR = 2.0), kidney cancer (OR = 2.1), prostate cancer (OR = 1.7) and thyroid cancer (OR = 1.9) (table 3) [8].

Table 3 Association between CHEK2 variants and selected types of cancer

Conclusions

It seems that CDKN2A, NOD2 and CHEK2 are responsible for a wide range of cancer types.

We estimate that the mutations mentioned above are responsible for around 20% of malignancies occurring in the Polish population. According to our studies over 4 million people in Poland carry one of the mutations described above. We elaborated genetic tests for CDKN2A, NOD2 and CHEK2 aimed at reliable identification of persons with increased risk of developing cancers of the breast, ovary, lung, prostate, thyroid, colon, kidney and malignant melanoma.

References

  1. 1.

    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, 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, in press.

    Google Scholar 

  2. 2.

    Debniak T, Gorski B, Huzarski T, Byrski T, Cybulski C, Mackiewicz A, Gozdecka-Grodecka S, Gronwald J, Kowalska E, Haus O, Grzybowska E, Stawicka M, Swiec M, Urbanski K, Niepsuj S, Wasko B, Gozdz S, Wandzel P, Szczylik C, Surdyka D, Rozmiarek A, Zambrano O, Posmyk M, Narod SA, Lubinski J: A common variant of CDKN2A (p16) predisposes to breast cancer. J Med Genet 2005, 42: 763–765. 10.1136/jmg.2005.031476

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  3. 3.

    Debniak T, Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, Zaluga E, Maleszka R, Kladny J, Gorski B, Cybulski C, Gronwald J, Kurzawski G, Lubinski J: CDKN2A common variants and their association with melanoma risk: a population-based study. Cancer Res 2005, 65: 835–839.

    CAS  PubMed  Google Scholar 

  4. 4.

    Lener MR, Oszutowska D, Castaneda J, Kurzawski G, Suchy J, Nej-Wolosiak K, Byrski T, Huzarski T, Gronwald J, Szymanska A, Szymanska-Pasternak J, Grodzki T, Serwatowski P, Bre Borowicz G, Scott RJ, Lubinski J: Prevalence of the NOD2 3020insC mutation in aggregations of breast and lung cancer. Breast Cancer Res Treat 2005, 1–5.

    Google Scholar 

  5. 5.

    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, 89: 91–93. 10.1007/s10549-004-1250-y

    Article  PubMed  Google Scholar 

  6. 6.

    Kurzawski G, Suchy J, Kladny J, Grabowska E, Mierzejewski M, Jakubowska A, Debniak T, Cybulski C, Kowalska E, Szych Z, Domagala W, Scott RJ, Lubinski J: The NOD2 3020insC mutation and the risk of colorectal cancer. Cancer Res 2004, 64: 1604–1606. 10.1158/0008-5472.CAN-03-3791

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Lubinski J, Huzarski T, Kurzawski G, Suchy J, Masojc B, Mierzejewski M, Lener M, Domagala W, Chosia M, Teodorczyk U, Medrek K, Debniak T, Złowocka 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: 59–63. 10.1186/1897-4287-3-2-59

    Article  CAS  Google Scholar 

  8. 8.

    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, 75: 1131–1135. 10.1086/426403

    PubMed Central  Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Tadeusz Dębniak.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dębniak, T., Cybulski, C., Kurzawski, G. et al. Low-risk Genes and Multi-organ Cancer Risk in the Polish Population. Hered Cancer Clin Pract 4, 52 (2006). https://doi.org/10.1186/1897-4287-4-1-52

Download citation

Keywords

  • CDKN24
  • CHEK2
  • NOD2
  • cancer risk