Open Access

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

  • Tadeusz Dębniak1Email author,
  • Cezary Cybulski1,
  • Grzegorz Kurzawski1,
  • Bohdan Górski1,
  • Tomasz Huzarski1,
  • Tomasz Byrski1,
  • Jacek Gronwald1,
  • Janina Suchy1,
  • Bartłomiej Masojć1,
  • Marek Mierzejewski1,
  • Marcin Lener1,
  • Urszula Teodorczyk1,
  • Krzysztof Mędrek1,
  • Elżbieta Złowocka1,
  • Ewa Grabowska-Kłujszo1,
  • Katarzyna Nej-Wołosiak1,
  • Anna Szymańska1,
  • Jolanta Szymańska-Pasternak1,
  • Joanna Matyjasik1,
  • Thierry van de Wetering1,
  • Anna Jakubowska1,
  • Oleg Oszurek1,
  • Aleksandra Tołoczko-Grabarek1,
  • Jennifer Castaneda1,
  • Rodney Scott1,
  • Steven A Narod1 and
  • Jan Lubiński1
Hereditary Cancer in Clinical Practice20064:52

DOI: 10.1186/1897-4287-4-1-52

Received: 10 December 2005

Accepted: 10 January 2006

Published: 15 January 2006

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

 

A148T

OR

95% Confidence Interval

p (adjusted p)

 

total controls (n = 3000)

105 (3.5%) G/A

     

bladder (n = 223)

0 (0%) A/A

7 (3.1%) G/A

0.9

0.4105-1.945

0.7764

(n.s)

colon (n = 724)

0 (0%) A/A

37 (5.1%) G/A

1.5

1.012-2.180

0.0423

(0.5499)

stomach (n = 246)

0 (0%) A/A

8 (3.3%) G/A

0.9

0.4461-1.925

0.8384

(n.s)

larynx (n = 396)

0 (0%) A/A

17 (4.3%) G/A

1.2

0.7326-2.088

0.4255

(n.s)

ovary (n = 340)

0 (0%) A/A

12 (3.5%) G/A

1.0

0.5491-1.853

0.9777

(n.s)

lung (n = 497)

0 (0%) A/A

34 (6.8%) G/A

2.0

1.358-3.018

0.0004

(0.0052)

prostate (n = 348)

0 (0%) A/A

13 (3.7%) G/A

1.1

0.5946-1.925

0.8215

(n.s)

kidney (n = 264)

0 (0%) A/A

6 (2.3%) G/A

0.6

0.2788-1.474

0.2915

(n.s)

thyroid (n = 173)

0 (0%) A/A

3 (1.7%) G/A

0.5

0.1528-1.549

0.2129

(n.s)

non-Hodgkin Lymphoma (n = 162)

0 (0%) A/A

6 (3.7%) G/A

1.1

0.4585-2.453

0.8909

(n.s)

breast (under 50 y) (n = 3318)

0 (0%) A/A

168 (5.1%) G/A

1.5

1.2764-1.832

0.002

 

melanoma (n = 471)

0 (0%) A/A

33 (7%) G/A

2.1

1.387-3.111

0.0003

 

pancreas (n = 210)

0 (0%) A/A

8 (3.8%) G/A

1.1

0.5246-2.273

0.8140

(n.s)

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

Site

Number tested

Number positive

Prevalence of 3020ins C (%)

Odds ratio

p-value

bladder

172

18

10.5

1.5

0.13

breast

462

37

8.0

1.1

0.62

with DCIS

126

18

14.3

2.1

0.009

without DCIS

336

19

5.7

0.76

0.30

colon

255

31

12.2

1.8

0.01

kidney

245

8

3.2

0.4

0.02

larynx

223

23

10.3

1.5

0.11

lung

258

30

11.6

1.7

0.03

melanoma

198

10

5.1

0.7

0.31

ovary

317

35

11.0

1.6

0.03

pancreas

127

6

4.7

0.6

0.37

prostate

298

17

5.7

0.76

0.40

stomach

213

20

9.4

1.3

0.27

thyroid

82

8

9.8

1.4

0.39

controls

1910

140

7.3

  
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

Site

No. tested

Number positive (prevalence), odds ratio, p-value

  

IVS2 + 1G>A

1100delC

Any truncating mutation

I157T

bladder

172

1 (0.6%) OR 1.2 p = 0.7

0

1 (0.6%) OR 0.8 p = 0.8

12 (7.0%) OR 1.5 p = 0.3

breast

1017

11 (1.1%) OR 2.3 p = 0.04

5 (0.5%) OR 2.0 p = 0.3

16 (1.6%) OR 2.2 p = 0.02

68 (6.7%) OR 1.4 p = 0.02

colon

300

1 (0.3%) OR 0.7 p = 0.9

2 (0.7%) OR 2.7 p = 0.4

3 (1%) OR 1.4 p = 0.8

28 (9.3%) OR 2.0 p = 0.001

kidney

264

0

2 (0.8%) OR 2.7 p = 0.5

2 (0.8%) OR 1.0 p = 0.8

26 (9.8%) OR 2.1 p = 0.0006

larynx

245

0

0

0

10 (4.1%) OR 0.8 p = 0.7

lung

272

0

0

0

7 (2.6%) OR 0.5 p = 0.1

melanoma

129

2 (1.5%) OR 3.3 p = 0.3

1 (0.8%) OR 3.1 p = 0.8

3 (2.3%) OR 3.2 p = 0.1

6 (4.6%) OR 1.0 p = 0.9

ovary

292

0

0

0

14 (4.8%) OR 1.0 p = 0.9

prostate

690

8 (1.2%) OR 2.5 p = 0.05

3 (0.4%) OR 1.7 p = 0.2

11 (1.6%) OR 2.2 p = 0.04

54 (7.8%) OR 1.7 p = 0.002

stomach

241

4 (1.7%) OR 3.5 p = 0.05

0

4 (2.1%) OR 2.3 p = 0.2

13 (5.4%) OR 1.1 p = 0.8

NHL

120

1 (0.8%) OR 1.8 p = 0.9

0

1 (0.8%) OR 1.1 p = 0.7

11 (9.2%) OR 2.0 p = 0.05

pancreas

93

0

0

0

6 (6.4%) OR 1.4 p = 0.6

thyroid

173

5 (2.9%) OR 6.2 p = 0.0003

1 (0.6%) OR 2.3 p = 0.9

6 (3.5%) OR 4.9 p = 0.0006

15 (8.7%) OR 1.9 p = 0.04

controls

4000

19 (0.475%)

10 (0.25%)

29 (0.725%)

193 (4.825%)

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.

Authors’ Affiliations

(1)
International Hereditary Cancer Center, Pomeranian Medical Univeristy

References

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Copyright

© The Author(s) 2006

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