Role of <i>GALNT12</i> in the genetic predisposition to attenuated adenomatous polyposis syndrome

<div><p>The involvement of <i>GALNT12</i> in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that <i>GALNT12</i> could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the <i>GALNT12</i> gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC.</p></div

List of CRC predisposition genes included in the NGS custom panel.

<p>List of CRC predisposition genes included in the NGS custom panel.</p

Clinical characteristics of c.907G>A, p.(D303N) carriers.

<p>Clinical characteristics of c.907G>A, p.(D303N) carriers.</p

Clinicopathological characteristics of study cohorts.

<p>Clinicopathological characteristics of study cohorts.</p

Adenomas tested for LOH and MUC1 IHC.

<p>Adenomas tested for LOH and MUC1 IHC.</p

Pedigrees of families harboring c.907G>A (p.D303N) and segregation analysis.

<p>Probands are marked with arrows. MUT = individual carrying the c.907G>A (p.D303N) allele. WT = individual not carrying the c.907G>A, p.(D303N) allele. CRC = colorectal cancer. y = age at diagnosis or age at the time of DNA extraction (in healthy subjects).</p

c.907G>A, p.(D303N) allelic population frequencies and association analysis.

<p>c.907G>A, p.(D303N) allelic population frequencies and association analysis.</p

Filtering strategy for the detection of candidate variants.

<p>Filtering strategy for the detection of candidate variants.</p

Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study.

Journal Article;BACKGROUND The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. METHODS Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. RESULTS Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7 % out of 966 post-implementation cycles compared with 23.1 % out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33 % pre-implementation vs. 44.5 % post-implementation cycles; p < 0.0001), diarrhea (74.0 % vs. 80.5 %; p = 0.011) and dyslipemia (25.0 % vs. 44.6 %; p < 0.001). CONCLUSIONS Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction.This study was funded by Pfizer, S.L.U. Medical writing assistance was provided by Esther Tapia, PhD and was founded by Pfizer.Ye