Determinación de los costos unitarios de la marca de puro Perdomo fresco

Germline CDH1 mutations were detected in 4% of the 499 families that were referred for testing by a clinical geneticist based on the suspicion of gastric cancer predisposition. The CDH1 mutation detection rate in families that met the 2010 HDGC criteria was 14% (16 of 118 families). Our results are in agreement with recent reports on CDH1 mutation testing in a diagnostic setting, in which

2 a detection rate of 18% and 19% (11/61 and 34/183 families fulfilling the 2010

HDGC criteria, respectively) was reported.13, 32

The current HDGC criteria and accompanying mutation detection rates of 30-

50% are based on small, highly selected series of gastric cancer patients.15, 16,

30, 33, 34 _{Most of these studies were published before 2010 and included families}

that fulfilled the original strict HDGC criteria: (i) two or more gastric carcinomas in first-degree relatives with at least one DGC diagnosed before age 50 or; (ii) three or more DGC in first-degree relatives diagnosed at any age. For these two criteria, the CDH1 mutation detection rate in our cohort is only 21% (13/63). This lower mutation detection rate might be due to lack of the founder mutation

described in a previous report15_{, the diagnostic setting with a low bias towards}

highly suspected families, and a strict categorization of missense mutations leading to less variants being classified as pathogenic or likely pathogenic. In 2010 two additional HDGC selection criteria were added: inclusion of individuals with DGC before the age of 40 without a family history, and inclusion of individuals and families with diagnoses of both DGC and LBC (one case below the age of 50).17 _{For these two additional criteria, when present without presence} of the original criteria, our mutation detection rate was 5% (3/55). Therefore these criteria increased the sensitivity, but decreased the mutation detection ratio from 20% to 14%. The detection rate in families with sufficient histology data but not meeting the HDGC selection criteria was only 0.4% (1/236). In the new criteria that are established by the IGCLC in 2015, the two first criteria (“Two or more gastric cancer cases in a family, one DGC<50” and “Three or more DGC cases regardless of age”) were merged into a new criterion: “Two or more gastric cancer cases regardless of age, at least one confirmed DGC, in first

and second degree relatives”.35 _{Because the age restriction is discarded, more}

families fulfill the criteria and become eligible for testing. Therefore, this new criterion implies a lower mutation detection rate. Nevertheless, it will lead to a higher sensitivity since more families will be identified. For our cohort, one additional mutation-positive and 58 additional mutation-negative families would fulfill the 2015 HDGC criteria (see column “New criterion: 2GC, 1 DGC” in Supplementary Table 2).

In our cohort, almost all CDH1-mutation positive families (16/18) fulfilled the

HDGC criteria as defined in 2010.17 _{In contrast, Benusiglio et al. found that}

39% of mutation carriers did not fulfill the HDGC criteria.32 _{They and other}

breast cancer (LBC) without DGC.32, 36-38 _{Based on these data, Petridis et al. and} Benusiglio et al. advise CDH1 mutation screening in women with bilateral LBC

and/or lobular carcinoma in situ without a family history of gastric cancer.32,

38 _{Schrader et al. screened 318 women with early-onset LBC or familial LBC}

for CDH1 mutations and found only four variants of uncertain significance. Therefore, they concluded that CDH1 mutations are at most infrequent in this

group.39 _{In the current study, no pathogenic CDH1 mutations were detected in}

22 LBC families without DGC (four of them with two cases of LBC under the age of 50). This is most likely explained by the number of families with exclusively LBC, which is relatively low in our cohort.

The ability to apply the HDGC criteria largely depends on the histological diagnosis. In our setting, the original histological classification was concordant with that of the review in 97% (175/181). However, in 21% of the available pathology specimens the histological type of gastric cancer was missing in the original report. The introduction of fixed-format pathology reporting in the Netherlands, using pathology reports that strictly follow pre-defined protocols including the histological classification, will probably reduce this issue in the near future. No CDH1 mutations were detected in 98 families that presented with intestinal-type or combined histological diagnoses of gastric cancer and only one CDH1 mutation was detected in the 77 families that could not be classified because of lack of pathological data, demonstrating the merit of selecting patients with diffuse-type gastric cancer for mutation testing.

Our study has a few limitations. First, the population studied consists of patients and relatives referred to a clinical geneticist by physicians who suspect genetic predisposition for gastric cancer. In the Netherlands, clinical geneticists, although affiliated to academic hospitals, counsel patients in outpatient clinics in many hospitals spread throughout the country. However, not all individuals at risk for CDH1 mutations are referred, and therefore, the sensitivity and specificity, as well as the positive- and negative-predictive values that were calculated may be overestimated. Second, we correlated the CDH1 mutation analysis results with clinicopathological data. Data were not complete for a relatively high number of individuals tested and were not available at all for relatives who did not consent to make medical reports available for genetic counseling. Therefore, shortage of data hampered categorization of a subset of families. Despite these limitations, our results are comparable to other recent studies who have performed similar analyses.13, 32

2 Our survival analysis showed that patients with DGC and germline CDH1

mutations had shorter survival times compared to other HDGC patients tested and the overall Dutch gastric cancer population. However, it should be noted that these results depend on univariate analyses without correction for tumor stage and included a relatively small number of CDH1 patients. Also, approximately half of the gastric cancer patients’ data regarding survival were unavailable and could therefore not be included in the survival analysis. To the best of our knowledge, no other studies examined the overall survival in gastric cancer patients with CDH1 mutations.

A positive family history is a strong and consistently reported risk factor for gastric cancer. CDH1 is the most important DGC susceptibility gene. Gastric cancer has also been associated with germline mutations in DNA mismatch repair genes,

TP53, APC, BRCA1/2, STK11 and PTEN.40-45 _{Nonetheless, the molecular basis for}

familial aggregation of gastric cancer remains largely unknown. Endoscopic surveillance strategy for families that fulfill the HDGC criteria, but in whom no pathogenic mutation can be identified, is complicated. The IGCLC recommends annual endoscopic screening with extensive biopsy taking (>30) in an expert centre (Cambridge protocol).17, 35 _{However, early-stage signet ring cell carcinoma} is difficult to visualize during gastroduodenoscopy with random biopsies. For CDH1 mutation carriers, Fujita et al. estimated a theoretical number of 3469 biopsies to be needed to assure 90% detection rate of at least one neoplastic focus.46 _{Lim et al. showed that it is possible to increase the yield of signet ring cell} carcinoma by adhering to the strict Cambridge protocol and found signet ring cell carcinomas in 14/22 patients with and 2/7 patients without CDH1 mutations

fulfilling the 2010 HDGC criteria.47 _{A portion of the mutation-negative HDGC}

families described in the current study are followed by gastroduodenoscopy in a research setting of which results are not available yet. We think that endoscopic screening in a research setting is important to gather information on these families and detect cancer in early stage. Ultimately, endoscopic findings could also lead to the identification of new HDGC predisposing mutations as was demonstrated by Majewski and Kluijt et al., in which endoscopic screening led to the detection of intramucosal signet ring cells in four individuals from a large family without a pathogenic CDH1 mutation, eventually leading to the

identification of a germline CTNNA1 mutation by exome sequencing.48

Taken together, this study shows both the strengths and limitations of the current HDGC criteria. Despite the positive predictive value of only 14%, in our cohort of patients suspected for a gastric cancer predisposition the HDGC

criteria have a high sensitivity of 89% and a high negative predictive value of 99% for finding a germline CDH1 mutation. When the histological gastric cancer subclassification is known, the HDGC criteria of 2010 seem to be an adequate tool for clinical geneticists to select patients for CDH1 mutation analysis. Although CDH1 mutations are exclusively found in patients with diffuse-type gastric cancer we feel that lack of data on pathological classification should not prohibit such testing.