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The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype.

Ruijs MW, Broeks A, Menko FH, Ausems MG, Wagner A, Oldenburg R, Meijers-Heijboer H, van't Veer LJ, Verhoef S - Hered Cancer Clin Pract (2009)

Bottom Line: The prevalence of CHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands.Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population.However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.

View Article: PubMed Central - HTML - PubMed

Affiliation: Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands. mwg.ruijs@vumc.nl

ABSTRACT

Background: CHEK2 has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence of CHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype.

Methods: We have screened 65 Dutch TP53-negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype.

Results: We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del.

Conclusion: Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.

No MeSH data available.


Related in: MedlinePlus

Pedigrees of germline CHEK2 sequence variation families. Square symbols indicate males, round symbols indicate females, line across symbol means deceased individual. Filled symbols indicate affected individuals with diagnosis confirmed by pathology reports. A quarterly filled symbol indicate affected individuals with diagnosis by family history. Tumour type and age at diagnosis of the tumours are indicated below the individual identifiers, d = age of death. The index patient is indicated with an arrow. Abd = abdominal cancer, B = breast cancer, Bl = bladder cancer, Br = brain tumour, C = colorectal cancer, cancer = cancer of unknown origin, DFS = dermatofibrosarcoma, End = endometrial cancer, Ho = Hodgkin lymphoma, Ki = kidney cancer, L = lung cancer, Leu = leukaemia, LMS = Leiomyosarcoma, O = ovarian cancer, Oes = oesophagus carcinoma, OS = osteosarcoma, RMS = rhabdomyosarcoma, Schw = schwannoma, SG = salivary gland cancer, Sk = skin cancer, St = stomach cancer, mut + = mutation detected, mut - = mutation excluded.
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Figure 1: Pedigrees of germline CHEK2 sequence variation families. Square symbols indicate males, round symbols indicate females, line across symbol means deceased individual. Filled symbols indicate affected individuals with diagnosis confirmed by pathology reports. A quarterly filled symbol indicate affected individuals with diagnosis by family history. Tumour type and age at diagnosis of the tumours are indicated below the individual identifiers, d = age of death. The index patient is indicated with an arrow. Abd = abdominal cancer, B = breast cancer, Bl = bladder cancer, Br = brain tumour, C = colorectal cancer, cancer = cancer of unknown origin, DFS = dermatofibrosarcoma, End = endometrial cancer, Ho = Hodgkin lymphoma, Ki = kidney cancer, L = lung cancer, Leu = leukaemia, LMS = Leiomyosarcoma, O = ovarian cancer, Oes = oesophagus carcinoma, OS = osteosarcoma, RMS = rhabdomyosarcoma, Schw = schwannoma, SG = salivary gland cancer, Sk = skin cancer, St = stomach cancer, mut + = mutation detected, mut - = mutation excluded.

Mentions: The c.1100delC in exon 10 of the CHEK2 gene, a mutation located in the kinase domain of the gene and abolishing the kinase activity of the protein, was detected in four index patients. In one family, a classical LFS family, the c.1100delC was detected in a patient who developed breast cancer at the age of 48 years (Figure 1A), which is in line with the c.1100delC acting as a low penetrance breast cancer susceptibility allele [19]. Relatives with a 50% chance of being a c.1100delC carrier in this family who had developed breast cancer were not available for testing. However, it is not likely to be the LFS-causing mutation in this family, considering the absence of the c.1100delC in the patient's son who developed a sarcoma at 15 years of age. In an LFL and LFS-suggestive family, the patients identified as carrying the c.1100delC had breast cancer (Figure 1B and 1D); in a fourth family, a LFS-suggestive family, the patient identified with the c.1100delC sequence variant had both breast and colorectal cancer (Figure 1C). No additional material was available for testing to see if and how the mutation segregates in these families. In all four of the c.1100delC families, this sequence variant seemed to be associated with breast cancer or breast and colorectal cancer, rather than LFS. The reported frequency of the CHEK c.1100delC in Dutch controls is 1.4%, in Dutch breast cancer patients not selected for family history 2.5% and in Dutch BRCA1/2-negative families with breast cancer 4.9%[19]. In our sample the frequency was 6.2% (4/65), significantly different from that for healthy controls (p = 0.006).


The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype.

Ruijs MW, Broeks A, Menko FH, Ausems MG, Wagner A, Oldenburg R, Meijers-Heijboer H, van't Veer LJ, Verhoef S - Hered Cancer Clin Pract (2009)

Pedigrees of germline CHEK2 sequence variation families. Square symbols indicate males, round symbols indicate females, line across symbol means deceased individual. Filled symbols indicate affected individuals with diagnosis confirmed by pathology reports. A quarterly filled symbol indicate affected individuals with diagnosis by family history. Tumour type and age at diagnosis of the tumours are indicated below the individual identifiers, d = age of death. The index patient is indicated with an arrow. Abd = abdominal cancer, B = breast cancer, Bl = bladder cancer, Br = brain tumour, C = colorectal cancer, cancer = cancer of unknown origin, DFS = dermatofibrosarcoma, End = endometrial cancer, Ho = Hodgkin lymphoma, Ki = kidney cancer, L = lung cancer, Leu = leukaemia, LMS = Leiomyosarcoma, O = ovarian cancer, Oes = oesophagus carcinoma, OS = osteosarcoma, RMS = rhabdomyosarcoma, Schw = schwannoma, SG = salivary gland cancer, Sk = skin cancer, St = stomach cancer, mut + = mutation detected, mut - = mutation excluded.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2664322&req=5

Figure 1: Pedigrees of germline CHEK2 sequence variation families. Square symbols indicate males, round symbols indicate females, line across symbol means deceased individual. Filled symbols indicate affected individuals with diagnosis confirmed by pathology reports. A quarterly filled symbol indicate affected individuals with diagnosis by family history. Tumour type and age at diagnosis of the tumours are indicated below the individual identifiers, d = age of death. The index patient is indicated with an arrow. Abd = abdominal cancer, B = breast cancer, Bl = bladder cancer, Br = brain tumour, C = colorectal cancer, cancer = cancer of unknown origin, DFS = dermatofibrosarcoma, End = endometrial cancer, Ho = Hodgkin lymphoma, Ki = kidney cancer, L = lung cancer, Leu = leukaemia, LMS = Leiomyosarcoma, O = ovarian cancer, Oes = oesophagus carcinoma, OS = osteosarcoma, RMS = rhabdomyosarcoma, Schw = schwannoma, SG = salivary gland cancer, Sk = skin cancer, St = stomach cancer, mut + = mutation detected, mut - = mutation excluded.
Mentions: The c.1100delC in exon 10 of the CHEK2 gene, a mutation located in the kinase domain of the gene and abolishing the kinase activity of the protein, was detected in four index patients. In one family, a classical LFS family, the c.1100delC was detected in a patient who developed breast cancer at the age of 48 years (Figure 1A), which is in line with the c.1100delC acting as a low penetrance breast cancer susceptibility allele [19]. Relatives with a 50% chance of being a c.1100delC carrier in this family who had developed breast cancer were not available for testing. However, it is not likely to be the LFS-causing mutation in this family, considering the absence of the c.1100delC in the patient's son who developed a sarcoma at 15 years of age. In an LFL and LFS-suggestive family, the patients identified as carrying the c.1100delC had breast cancer (Figure 1B and 1D); in a fourth family, a LFS-suggestive family, the patient identified with the c.1100delC sequence variant had both breast and colorectal cancer (Figure 1C). No additional material was available for testing to see if and how the mutation segregates in these families. In all four of the c.1100delC families, this sequence variant seemed to be associated with breast cancer or breast and colorectal cancer, rather than LFS. The reported frequency of the CHEK c.1100delC in Dutch controls is 1.4%, in Dutch breast cancer patients not selected for family history 2.5% and in Dutch BRCA1/2-negative families with breast cancer 4.9%[19]. In our sample the frequency was 6.2% (4/65), significantly different from that for healthy controls (p = 0.006).

Bottom Line: The prevalence of CHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands.Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population.However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.

View Article: PubMed Central - HTML - PubMed

Affiliation: Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands. mwg.ruijs@vumc.nl

ABSTRACT

Background: CHEK2 has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence of CHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype.

Methods: We have screened 65 Dutch TP53-negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype.

Results: We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del.

Conclusion: Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.

No MeSH data available.


Related in: MedlinePlus