De novo germline pathogenic variant in Lynch Syndrome: A rare event or the tip of the iceberg?

Lynch Syndrome is an autosomal dominant cancer predisposition syndrome caused by germline pathogenic variants or epimutation in one of the DNA mismatch repair genes. De novo pathogenic variants in mismatch repair genes have been described as a rare event in Lynch Syndrome (1-5%), although the prevalence of de novo pathogenic variants in Lynch Syndrome is probably underestimated. The de novo pathogenic variant was identified in a 26-year-old woman diagnosed with an adenocarcinoma of the caecum with mismatch repair protein deficiency at immunohistochemistry and a synchronous neuroendocrine tumor of the appendix with normal expression of mismatch repair proteins. DNA testing revealed deletion of exon 6 of the MLH1 gene. It appeared to be a de novo event, as the deletion was not detected in the patient's parents. The presence of a mosaicism in the patient was excluded and haplotype analysis demonstrated the paternal origin of the chromosome harboring the deletion. The de novo deletion probably originated either from a very early postzygotic or a single prezygotic mutational event, or from a gonadal mosaicism. In conclusion, the identification of de novo pathogenic variants is crucial to allow proper genetic counseling and appropriate management of the patient's family.

Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma.

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42-77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.

Rare variants in XRCC2 as breast cancer susceptibility alleles.

BACKGROUND: Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation. METHODS: The coding regions and exon-intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms. RESULTS: The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls. CONCLUSIONS: Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer.

Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. METHODS: We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. RESULTS: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. CONCLUSION: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

Pneumatosis cystoides of the right colon: a possible source of misdiagnosis. Report of a case.

Pneumatosis cystoides intestinalis is a rare condition that can be located in any part of the gastrointestinal tract. It is usually associated with a wide variety of gastrointestinal or pulmonary diseases. The primitive form is much less frequent and usually involves the left colon. The pathogenesis of pneumatosis cystoides intestinalis is still unclear. The mechanical theory, which is the most accepted explanation, postulates that gas is forced into the bowel wall by breaks in the mucosa; this is more likely to occur when the intraluminal pressure is higher, as happens in obstructive conditions, during endoscopies, or during infections from gas-forming bacteria. Pneumatosis cystoides is often asymptomatic, representing an occasional finding during investigations for other abdominal conditions. Complications occur in about 3% of cases and include obstruction, intussusception, volvulus, haemorrhage and intestinal perforation. When presenting acutely or in association with other abdominal conditions the differential diagnosis is rarely a problem. More important is to diagnose asymptomatic primitive submucosal pneumatosis of the colon, in order to avoid unnecessary intestinal resections. The Authors present the case of a patient with pneumatosis coli who underwent laparotomy for a suspected colonic lipomatosis of the right colon.

Solitary necrotic nodule of the liver: diagnostic and therapeutic considerations regarding a case.

Solitary necrotic nodule is a rare benign lesion of the liver of unknown aetiology, which as a result of its radiological features can be misdiagnosed as a necrotic tumour. We believe that surgical exploration with a limited liver resection and an extemporary examination of the specimen is the best strategy for this rare type of lesion.

Synchronous colorectal and renal carcinomas. Is it a definite clinical entity?

The aim of the study was to assess the frequency of synchronous colorectal and renal cancers among our patients. To this end we reviewed 781 consecutive patients operated on for colorectal carcinoma in our institution. Three patients (0.4%) had diagnosis of synchronous renal-cell cancer during the work-up for their colorectal primary tumours. The colon and rectum are frequently affected by multiple malignant tumours. Second primaries are not frequently associated with colorectal cancer. On the other hand, renal cell carcinoma has been described as being associated with other synchronous malignancies in up to 27.4% of cases. A recent report has described a 4.8% incidence of synchronous colorectal and renal carcinomas, which is much higher than that previously reported in the literature (0.03-0.5%). We found a 0.4% incidence of simultaneous colorectal cancer and renal cell carcinoma. The latter was invariably asymptomatic and diagnosed during the work-up for the colorectal cancer. We are unable to confirm the observation of a higher than expected incidence of synchronous colorectal and renal neoplasms. Nevertheless, the surgeon should be conscious of this association, when considering renal lesions detected during the work-up for colorectal cancer.

Primary hydatid cysts of psoas muscle.

BACKGROUND: Hydatid cysts may occur in any area of the body, but they usually localize to the liver and the lungs. Primary localization in muscle is not common, accounting for 2-3% of all sites; even rarer is the development of multiple cysts. METHODS: The patient presented with a painless abdominal mass which gradually increased in size to a diameter of approximately 16 cm. Organ imaging scan revealed multiple hydatid cysts within the right psoas muscle. Because of the proximity of the lesions to the iliac vessels, ureter and nerves to the lower limb, percutaneous drainage and alcoholization under local anaesthesia were -performed with the aim of reducing the size of the cysts and sterilizing them prior to definitive surgery. This procedure was not effective. Two weeks after percutaneous treatment the patient underwent surgery. RESULTS: At operation the cysts were localized and successfully removed under ultrasound guidance. Postoperative stay was -uneventful. Two years after surgery the patient has no evidence of recurrent hydatid disease. CONCLUSIONS: Ultrasonography is the preferred method for detecting muscular hydatid cyst and for guiding the surgeon during resection.