CHEK2 Is a Multiorgan Cancer Susceptibility Gene

Cybulski, Cezary; Górski, Bohdan; Huzarski, Tomasz; Masojć, Bartłomiej; Mierzejewski, Marek; Dębniak, Tadeusz; Teodorczyk, Urszula; Byrski, Tomasz; Gronwald, Jacek; Matyjasik, Joanna; Złowocka, Elżbieta; Lenner, Marcin; Grabowska, Ewa; Nej, Katarzyna; Castañeda, Jennifer; Mędrek, Krzysztof; Szymańska, Anna; Szymańska, Jolanta; Kurzawski, Grzegorz; Suchy, Janina; Oszurek, Oleg; Witek, Andrzej; Narod, SA; Lubiński, Jan

doi:10.1086/426403

Cited by 434 publications

(453 citation statements)

References 17 publications

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“…25,72 These mutations caused early stop codons with complete loss of protein expression. In contrast, tumours harbouring CHEK2 missense mutations, including I157T, shown to infer a marginal elevated risk of breast cancer, 71 seemed to respond normally to therapy. Among tumours resistant to anthracyclines lacking mutations in either TP53 or CHEK2, we found low ATM expression levels (but not ATM mutations) to predict anthracycline/mitomycin resistance.…”

Section: Other Genes Involved In the P53 Pathwaymentioning

confidence: 95%

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Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Section: Other Genes Involved In the P53 Pathwaymentioning

confidence: 95%

“…69 However, truncating (but not missense) CHEK2 mutations, the most common being the del1100C variant detected in 0.5-1% of north-eastern Europeans, are associated with a 2-to 3-fold elevated risk of breast cancer, 70,71 as well as other tumour forms, such as cancers of the thyroid and prostate.…”

Section: Other Genes Involved In the P53 Pathwaymentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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“…SPT may also occur due to the presence of genetic base, especially the multiorgan susceptibility gene, the CHEK2 protein, which participates in the DNA damage. The missence variant 1157 T was associated with an increased risk of cancers of breast, colon, kidney, prostate and thyoid [2]. In some studies, an increased incidence of breast cancer is seen in women with thyroid carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Multiple Metachronous Malignancies, One Patient with Three Primary Malignancies

Jayaraman¹,

Sadasivam²,

Rao³

2011

Indian J Surg

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Development of a primary cancer after treatment of the first with radiotherapy or chemotherapy is well documented, but it is common with hematological malignancies. Variety of reasons are suggested by various researchers, but a conclusive evidence is not yet available. Excepting a few correlations like the tamoxifen therapy and endometrial cancer, angiosarcoma of the breast following radiotherapy, occurrence of other metachronous malignancies seem to be dependent on genetic and environmental factors. A patient with three primary malignancies is presented here. Keywords Multiple malignancies . Metachronous . Gene disorders Case ReportA 54 year old female presented with a painless swelling in the anterior part of the neck for over 3 years' duration. On examination, the swelling was globular measuring about 3 cm in diameter in the region of right lobe of thyroid and was moving with deglutition. There was no retrosternal extension and cervical lymphadenopathy. A clinical diagnosis of thyroid adenoma was made. Right hemithyroidectomy was done, and the histopathology was minimally invasive follicular carcinoma of thyroid. She was suggested completion thyroidectomy which she refused. By the end of 1 year, she developed swelling of the left lobe, which on CT showed calcified deposits, and the FNAC showed scanty colloid material with follicular cells with no evidence of malignancy. She was lost to follow up since then.Five years after right hemithyroidectomy, she developed a malignant lump in the left breast, for which she underwent simple mastectomy with axillary clearance. Six courses of adjuvant chemotherapy (Cyclophosphamide, Epirubicin and 5 flurouracil) was given, and was advised to take Tamoxifen for 5 years.A year after mastectomy, during regular follow up, the abdominal ultrasound showed thickened endometrium of about 13 mm. On curettage, it was well differentiated adenocarcinoma, for which she refused any treatment. At this point, Tamoxifen was stopped and Letrozole was started.About 18 months after mastectomy, she developed hard nodules on the mastectomy scar, which were histologically proved to be infiltrating duct carcinoma. On further investigations, her CTs showed multiple hypodense lesions of varying size with variegated post contrast enhancement in the arterial phase in the liver, metastatic deposits in the lungs and pleural effusion (Fig. 1), though she remained asymptomatic. Only treatment she accepted was the local radiotherapy for the recurrent nodules, for which 56 Gy of radiation was given to the chest wall. In the meantime, she developed abdominal distension due to ascites, which showed malignant cells. She later succumbed to further complications. DiscussionMultiple metachronous primary cancers are known to occur in an individual, but it is often seen with hematological malignancies of childhood. The reasons are many; BRCA gene mutation, viral cause like HPV

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“…20,21 Given that CHEK2 mutations have been seen to increase risks of thyroid, ovarian, kidney, and colon cancer, we advised screening for these cancers in the context of a positive family history of these cancers. [22][23][24] The patient elected care at an outside institution and her follow-up is unknown.…”

Section: Discussionmentioning

confidence: 99%