Case report of a woman with monoclonal gammapathy and papillary thyroid carcinoma, diagnosed because of detection of CHEK2 (I157T) mutation in genetic examinations

The CHEK2 gene encodes the CHK2 protein, which is kinase involved in DNA repair processes. By activating a lot of cell substrates, it can regulate the cell cycle, demonstrates suppressive effects, and participates in the senescence and apoptosis processes. Mutations in the CHEK2 gene are associated with increased risk of numerous cancers. The case described herein is that of a woman with a missense mutation that results in the substitution of isoleucine for threonine at position 157. This variant of the mutation doubles the risk of papillary thyroid carcinoma two times and causes up to 9% of these cancer. It is also associated with a two-fold increased risk of cancers of the kidney (10%), colon (10%), and ovary (10% - G1), a 1.6-fold increased risk of prostate cancer (8% of all of them and 12% of familiar ones), and a 1.5-fold increased risk of breast cancer (7%). The screening procedures were initiated in a carrier who revealed papillary thyroid carcinoma. Genetic screening of the family diagnosed her daughter as the carrier of this mutation. Until now no active cancer disease has been recognized in the daughter. On the example of the presented case we discuss indications for screening in cases of positive family history. The group especially predisposed seem to be patients with at least two coexisting carcinomas. Having diagnosed the mutation, it is necessary to do genetic screening of family members. Continuous oncological observation of the carriers of CHEK 2 mutation is essential. (Pol J Endocrinol 2010; 61 (5): 502-506)Ludzki gen CHEK2 koduje białko CHK2, będące kinazą efektorową zaangażowaną w naprawę DNA. Aktywując wiele substratów komórkowych, bierze udział w regulacji cyklu komórkowego, wykazuje działanie supresyjnie, wpływa również na proces apoptozy i starzenia się komórek. Mutacje genu CHEK2 są związane z ryzykiem licznych nowotworów. Opisywany przypadek chorej dotyczy mutacji typu missens, gdzie dochodzi do zamiany izoleucyny na treoninę w pozycji 157. Mutacja ta zwiększa 2-krotnie ryzyko raka brodawkowatego tarczycy. Predysponuje do występowania 2-krotnie częściej raka nerki (10%), jelita grubego (10%), jajnika (10% - G1), 1,6-krotnie częściej raka prostaty (8% wszystkich i 12%występujących rodzinnie) oraz 1,5-krotnie częściej raka piersi (7%). Na podstawie diagnostyki w kierunku predysponowanych nowotworów wykryto u chorej raka brodawkowatego tarczycy. Skrining genetyczny rodziny pozwolił na wykazanie nosicielstwa tej mutacji u córki pacjentki - dotychczas nie stwierdzono u niej czynnej choroby nowotworowej. Opisywany przypadek chorej wskazuje na celowość przeprowadzania badań genetycznych w przypadku dodatniego wywiadu rodzinnego w kierunku chorób nowotworowych. Szczególnie predysponowaną grupą wydają się być chorzy z co najmniej dwoma współistniejącymi nowotworami. Wykazanie mutacji nakłada obowiązek badań genetycznych u pozostałych członków rodziny, jak również bezterminowy nadzór onkologiczny u nosicieli mutacji. (Endokrynol Pol 2010; 61 (5): 502-506

<i>BRCA1</i> founder mutations and beyond in the Polish population: A single-institution <i>BRCA1/2</i> next-generation sequencing study

<div><p>Hereditary mutations in <i>BRCA1/2</i> genes increase the risk of breast cancer by 60–80% and ovarian cancer by about 20–40% in female carriers. Detection of inherited mutations in asymptomatic carriers allows for the implementation of appropriate preventive measures. <i>BRCA1/2</i> genotyping is also important for poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitor administration. This work addresses the need for next-generation sequencing (NGS) technology for the detection of <i>BRCA1/2</i> mutations in Poland where until recently mostly founder mutations have been tested, and whether <i>BRCA</i> diagnostics should be extended beyond the panel of founder mutations in this population. The study comprises 2931 patients who were referred for genetic counseling and tested for founder and recurrent mutations in <i>BRCA1</i> (5382insC (c.5266dupC; p.Gln1756Profs), c.5370C>T (c.5251C>T; p.R1751*), 300T>G (c.181T>G; p.Cys61Gly), 185delAG (c.68_69delAG; p.Glu23Valfs), and 4153delA (c.4035delA; p.Glu1346Lysfs)) by high-resolution melting/Sanger sequencing. A total of 103 (3.5%) mutations were detected, including 53 (51%) in healthy subjects and 50 (49%) in cancer patients. Then, based on more stringent clinical and pedigree criteria, sequencing of all <i>BRCA1/2</i> exons was performed in 454 (16%) patients without founder mutations by NGS, which detected 58 mutations (12.8%), 40 (8.8%) of which were pathogenic. In 14 (3.1%) subjects, variants of uncertain significance (VUS) were detected, and in four (0.9%) subjects, the detected mutations were benign. In total, 161 mutations were detected using our two-step algorithm (founder test and NGS), of which 64% were founder mutations, 25% were NGS-detected pathogenic mutations, 9% were VUS, and 2% were benign. In addition, 38 mutations not yet reported in the Polish population were detected. In total, founder mutations accounted for only 64% of all detected mutations, and the remaining mutations (36%) were dispersed across the <i>BRCA1/2</i> gene sequences. Thus, in Poland, testing for constitutional mutations in <i>BRCA1/2</i> should be carried out in two stages, where NGS is performed in qualifying subjects if founder mutations are not identified.</p></div

Frequencies of mutations detected with the screening test targeting founder and recurrent <i>loci</i> in <i>BRCA1</i> per year and total.

<p>Frequencies of mutations detected with the screening test targeting founder and recurrent <i>loci</i> in <i>BRCA1</i> per year and total.</p

Percentage share of all detected mutations with both the screening test (103) and NGS (58): Pathogenic (40), VUS (14), benign (4).

<p>Percentage share of all detected mutations with both the screening test (103) and NGS (58): Pathogenic (40), VUS (14), benign (4).</p

The frequency of mutations detected in <i>BRCA1/2</i> with NGS among 454 individuals, per year and total (2014–2016).

<p>The frequency of mutations detected in <i>BRCA1/2</i> with NGS among 454 individuals, per year and total (2014–2016).</p