Lidia Kasprzak

Familial medullary thyroid carcinoma and prominent corneal nerves associated with the germline V804M and V778I mutations on the same allele of RET

Editor—Germline mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia (MEN) type 2A, 2B, and familial medullary thyroid carcinoma (FMTC). MEN 2A is characterised primarily by medullary thyroid carcinoma (MTC), parathyroid hyperplasia, and phaeochromocytoma. MEN 2B has additional stigmata including a marfanoid habitus, mucosal neuromas, and corneal nerve thickening. In FMTC, the only lesion present is MTC. Although characteristic of MEN 2B, prominent corneal nerves have been noted in subjects with MEN 2A. We have studied a family presenting with MTC and corneal nerve thickening (CNT), but no evidence of MEN 2 related disease outside the thyroid gland (fig 1). The proband (III.1) was found to have prominent corneal nerves on routine ophthalmological examination in his late 30s. No further action was taken and he presented with a palpable thyroid mass at the age of 53. Figure 1 A truncated pedigree of the family is shown. Filled symbols indicate affected subjects. The letters below the symbols refer to the site of cancer, the numbers following the abbreviations indicate age at diagnosis. MTC, medullary thyroid cancer; PSU, primary site unknown; d, age at death; CNT, corneal nerve thickening. MEN 2B was suspected and he was referred for laboratory screening tests for MTC and phaeochromocytoma. Serum calcitonin was raised at 4090 ng/l (normal range <60 ng/l). Serum calcium and phosphorus were normal. Twenty four hour urinary total catecholamine, metanephrine, and vanillylmandelic acid levels were within normal limits. A thoracic and abdominal CT scan performed before surgery was normal and scanning of the neck confirmed the presence of the right thyroid mass. The patient underwent a total thyroidectomy and pathological examination indicated bilateral MTC with extension beyond the capsule. His endocrinologist referred him for a genetic evaluation with a diagnosis of MEN 2B. However, other than CNT, he and his relatives …

Fortnightly review: Hereditary ovarian carcinoma

Ovarian carcinoma is the fourth most common cause of cancer death in women in Western countries. Because of inadequate screening methods and the vague nature of the symptoms, patients present late in the course of the disease and the survival rate is poor. There are no strong environmental risk factors, and after age is controlled for the most important risk factor is a family history of ovarian carcinoma. The effect of a positive family history on a womans risk of ovarian carcinoma is illustrated in table 1. In this review we focus on the hereditary aspects of ovarian carcinoma. #### Summary points We reviewed original articles and expert reviews from journals cited in Medline between 1980 and 1998 and supplemented this information with unpublished data from our colleagues. We also included information from recently published books. In performing the Medline searches we used the following key words: hereditary ovarian carcinoma, breast and ovarian carcinoma syndrome, ovarian cancer screening, prophylactic oophorectomy. Between 5% and 10% of cases of ovarian carcinoma are the result of an inherited gene or genes. The percentage depends on the degree of relatives included in the calculation and the method of case ascertainment.2 Narod et al …

Deletion of 22q11 in two brothers with different phenotype

We have studied two brothers with submicroscopic 22q11 deletion. One brother had findings suggestive of DiGeorge syndrome, while the other had milder anomalies, including polydactyly. Fluorescence in situ hybridization (FISH) showed a minor cell line with deletion 22q11 in the mother. To our knowledge, this is the first report of a deletion of 22q11 in two sibs with different phenotypes and apparent maternal mosaicism detected with FISH. This family illustrates the variability of the syndrome and further demonstrates the possibility of gonadal mosaicism for a microdeletion. Prenatal diagnosis may be offered after the birth of a child with a 22q11 deletion, even in the absence of parental chromosomal anomalies.

High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families.

Lynch syndrome is one of the most common autosomal dominantly inherited cancer syndromes. Mutations in MLH1, MSH2, MSH6, and PMS2 account for greater than 98% of reported mutations in Lynch syndrome families. It has been reported that large genomic deletions in MLH1 and MSH2 are a frequent cause of Lynch syndrome in certain populations. Using a multimodal approach, we have identified mutations in MLH1, MSH2, and MSH6 in French Canadian families fulfilling the Amsterdam criteria for Lynch syndrome and who displayed abnormal staining for at least one of the Lynch syndrome proteins. Mutations were identified in 28 of our 29 French Canadian probands (97%). A total of 18 distinct mutations (nine in MLH1, seven in MSH2, two in MSH6) were identified, of which six (33%) were genomic exon deletions. Another four (22%) resulted in exon deletions in cDNA alone. Three (17%) are novel mutations. Five of these 18 mutations were detected in more than one distinct family (four in MLH1, one in MSH2) and haplotype analysis suggests the possibility of founder effects. Fifteen of the 29 (52%) families carried one of these five putative founder mutations. These findings may simplify genetic testing for Lynch syndrome in French Canadians.

Invasive breast cancer following bilateral subcutaneous mastectomy in a BRCA2 mutation carrier: a case report and review of the literature

BackgroundPrimary prevention of breast cancer through prophylactic mastectomy can reduce the risk of malignancy in high-risk individuals. No type of mastectomy completely removes all breast tissue, but a subcutaneous mastectomy leaves more tissue in situ than does a simple mastectomy.Case presentationWe report a case of invasive breast cancer in a BRCA2-positive woman 33 years after bilateral subcutaneous mastectomy. To our knowledge, only one case of primary breast cancer after prophylactic mastectomy in a BRCA1-positive patient has been reported in the literature and none in BRCA2-positive individuals.ConclusionCareful documentation and long follow-up is essential to fully assess the benefits and risks of preventive surgical procedures in BRCA1 and BRCA2 mutation carriers.

I1307K APC and hMLH1 mutations in a non-Jewish family with hereditary non-polyposis colorectal cancer

We describe a French Canadian hereditary non‐polyposis colorectal cancer (HNPCC) kindred which carries a novel truncating mutation in hMLH1. Interestingly, the I1307K APC polymorphism, associated with an increased risk of colorectal cancer, is also present in this family. The I1307K polymorphism has previously only been identified in individuals of self‐reported Ashkenazi Jewish origins. In addition, in this family, there appears to be no relationship between the I1307K polymorphism and the presence or absence of cancer.

Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population

We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430–656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec.

A survey of APC mutations in Quebec.

This is an 11-year survey of molecular analysis of APC germline mutations for the province of Quebec done at the Molecular Pathology Unit of the Jewish General Hospital which offers genetic testing for hereditary forms of colorectal cancer for the whole of Quebec province. We report on 47 unique mutations seen in 66 families affected with familial adenomatous polyposis. Of these unique mutations, 60% are short indels, 28% are point mutations, and 6% are whole exon deletions. The absence of founder mutations and the variety of mutations encountered reinforce the value of RNA-based testing and the need for gene dosage techniques such as multiplex ligation-dependent probe amplification.

Multiple primary malignancies in a patient with situs ambiguus

To the Editor: Mrs D. is a 59 years old white female, with multiple metachronous cancers. She was initially diagnosed with stage I adenocarcinoma of the sigmoid colon at age 41. Over subsequent years, she had roughly 30 additional villous and tubulovillous adenomas, excised endoscopically and surgically. At 57, she had a second focally invasive adenocarcinoma of the transverse colon, treated by subtotal colectomy. There were no hyperplastic or hamartomatous colorectal polyps. Aside from gastrointestinal neoplasms, Mrs D. was also diagnosed with bladder (transitional cell) cancer at 47, a benign meningioma of the frontal lobe and a basal cell carcinoma of the right cheek at 48, a moderately differentiated squamous cell carcinoma of unknown primary affecting a cervical lymph node at 55 and a stage I invasive ductal carcinoma of the right breast (ER/PR positive, HER2/neu negative) at the age of 58 years. The patient’s past medical history included hypertension, dyslipidaemia, intradermal nevi and multiple seborrheic keratoses. At age 49, an incidental diagnosis of abdominal heterotaxia was made, on a CT scan performed to evaluate post-operative pain. The findings included a centrally placed liver, with a right-sided stomach, as well as multiple right-sided spleens. The heart was noted to be in its usual left-sided position. There was no extensive family history of cancer or laterality disorders, aside from her father who had gastric cancer at 53, and a maternal aunt with breast cancer at 70. Immunohistochemistry of both colonic cancers and several colonic polyps revealed no loss of expression of MLH1, MSH2, MSH6 or PMS2 gene products, implicated in the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Protein truncation testing (PTT) of stored blood RNA also failed to identify any truncating mutations in MLH1, MSH2, or MSH6 genes. No adenomatous polyposis coli (APC) gene mutations were found by PTT or DNA sequencing. Full sequencing of the MYH gene, associated with multiple colorectal adenomas, also failed to identify mutations. Karyotyping using G and Q-banding was normal (46, XX). There were no disease-causing BRCA1 or BRCA2 mutations (Myriad Genetics Laboratory). TP53 is currently under investigation.

Putative common origin of two MLH1 mutations in Italian-Quebec hereditary non-polyposis colorectal cancer families

Hereditary non‐polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3–5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.