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Background <p>The genetic background of ductal carcinoma in situ (DCIS) has not been well explored. Previously, we reported that Polish founder mutations of <i>BRCA1/2</i> confer susceptibility to DCIS. The aim of our study was to investigate the role of <i>CHEK2</i>, <i>PALB2</i>, <i>NBN</i> and <i>RECQL</i> mutations in the ethology of DCIS.</p> Methods <p>We studied 564 Polish women with DCIS for eight Polish founder alleles, including four in <i>CHEK2</i> (c.1100delC, c.444 + 1G &gt; A, del5395 and c.470T &gt; C), two in <i>PALB2</i> (c.509_510delGA and c.172_175delTTGT), one in <i>NBN</i> (c.657_661delACAAA) and one in <i>RECQL</i> (c.1667_1667 + 3delAGTA). To investigate the association of these alleles with DCIS risk, we used mutation frequencies in cancer-free controls as a reference (4000 to 4702 controls for different variants). To analyze survival, patients were followed on average for 156 months.</p> Results <p>A <i>CHEK2</i> mutation (all variants combined) was associated with an increased risk of DCIS (OR = 1.7, <i>p</i> = 0.003). The risk was higher for <i>CHEK2</i> truncating mutations (OR = 3.0, <i>p</i> = 0.001) than for a missense variant c.470T &gt; C (OR = 1.5, <i>p</i> = 0.04). The risk was highest for carriers of <i>CHEK2</i> truncating mutations with a family history of breast cancer (OR = 4.2, <i>p</i> = 0.01). There were no deaths reported in 52 <i>CHEK2</i> mutation carriers during the follow up time. <i>PALB2</i>, <i>NBN</i> and <i>RECQL</i> mutations were rare among cases and were not associated with DCIS risk in Polish women.</p> Conclusions <p>Based on the current study, women with a <i>CHEK2</i> mutation face an increased risk of DCIS. The presence of DCIS should be considered during surveillance of <i>CHEK2</i> mutation carriers. On the other hand, DCIS patients should receive genetic counseling and testing for <i>CHEK2</i> mutations.</p>

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Association analysis of germline mutations in CHEK2, PALB2, NBN and RECQL with the risk of ductal carcinoma in situ in Polish women

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月6日

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  • Sylwia Feszak,
  • Wojciech Kluźniak,
  • Igor Feszak,
  • Magdalena Chady,
  • Dominika Wokołorczyk,
  • Klaudia Stempa,
  • Helena Rudnicka,
  • Katarzyna Gliniewicz,
  • Anna Jakubowska,
  • Marcin Lener,
  • Maciej Czepukowicz,
  • Tomasz Huzarski,
  • Tadeusz Dębniak,
  • Jacek Gronwald,
  • Jan Lubiński,
  • Cezary Cybulski

摘要

Background

The genetic background of ductal carcinoma in situ (DCIS) has not been well explored. Previously, we reported that Polish founder mutations of BRCA1/2 confer susceptibility to DCIS. The aim of our study was to investigate the role of CHEK2, PALB2, NBN and RECQL mutations in the ethology of DCIS.

Methods

We studied 564 Polish women with DCIS for eight Polish founder alleles, including four in CHEK2 (c.1100delC, c.444 + 1G > A, del5395 and c.470T > C), two in PALB2 (c.509_510delGA and c.172_175delTTGT), one in NBN (c.657_661delACAAA) and one in RECQL (c.1667_1667 + 3delAGTA). To investigate the association of these alleles with DCIS risk, we used mutation frequencies in cancer-free controls as a reference (4000 to 4702 controls for different variants). To analyze survival, patients were followed on average for 156 months.

Results

A CHEK2 mutation (all variants combined) was associated with an increased risk of DCIS (OR = 1.7, p = 0.003). The risk was higher for CHEK2 truncating mutations (OR = 3.0, p = 0.001) than for a missense variant c.470T > C (OR = 1.5, p = 0.04). The risk was highest for carriers of CHEK2 truncating mutations with a family history of breast cancer (OR = 4.2, p = 0.01). There were no deaths reported in 52 CHEK2 mutation carriers during the follow up time. PALB2, NBN and RECQL mutations were rare among cases and were not associated with DCIS risk in Polish women.

Conclusions

Based on the current study, women with a CHEK2 mutation face an increased risk of DCIS. The presence of DCIS should be considered during surveillance of CHEK2 mutation carriers. On the other hand, DCIS patients should receive genetic counseling and testing for CHEK2 mutations.