Françoise Desseigne

Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome characterized by familial predisposition to colorectal carcinoma and extracolonic cancers of the gastrointestinal, urological, and female reproductive tracts. This dominant disorder is caused by germline defects in one of at least five DNA mismatch repair (MMR) genes: hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 (GTBP). Germline mutations of hMSH2 and hMLH1 are also frequently identified in families not fulfilling all the Amsterdam criteria, thereby demonstrating that the involvement of these genes is not confined to typical HNPCC. To evaluate the respective involvement of the various MMR genes in typical and incomplete HNPCC syndromes, we have performed an analysis of the hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in a large series of French kindreds (n=75) with colorectal tumors and/or aggregation of extracolonic cancers belonging to the HNPCC spectrum. Mutational analysis has been performed in all families, without preselection for the tumor phenotype. We have detected 26 pathogenic germline mutations of the hMLH1 and hMSH2 genes and several novel variants of the hPMS1, hPMS2, and hMSH6 genes. Our data confirm that, regardless of the type of families and the tumor phenotype, hPMS1, hPMS2, and hMSH6 germline mutations are rare in familial aggregation of colorectal cancers. Furthermore, they suggest that the presence of multiple primary malignancies in a single individual and the observation of extracolonic tumors in relatives of a colorectal cancer patient should be included among the guidelines for referring patients for genetic testing.

Estimating cancer risk in HNPCC by the GRL method

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome caused by germline mutations of the mismatch repair (MMR) genes. Only a few studies have taken into account the selection of families tested for these mutations in estimating colorectal cancer (CRC) risk in carriers. They found much lower estimates of CRC risks than previous ones, but these estimates lacked precision despite the large number of families. The aim of this study was to evaluate the efficiency of the ‘genotype restricted likelihood’ (GRL) method that provides unbiased estimates of risks whatever the ascertainment process of families, and to estimate CRC and endometrial cancer risk for carriers of the MMR genes. Efficiency of the GRL method was evaluated using simulations. Risks were estimated from a sample of 36 families diagnosed with HNPCC and carrying a mutation of MSH2 or MLH1, ascertained through a cancer family clinic in Lyon (France). The efficiency of the GRL method was found to be strongly dependent on the proportion of family members tested. By age 70 years, CRC risk was estimated at 47% (95% confidence interval: 12–98%) for men and 33% (95% confidence interval: 24–54%) for women. The endometrial cancer risk was only 14% (confidence interval: 6–20%). As methods allowing for the selection of families lack efficiency, large-scale family studies should be undertaken and data should be pooled to provide reliable and precise estimates of risks for an optimal familial management.

Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families.

Hereditary non‐polyposis colon cancer (HNPCC) is a common hereditary disease characterized by a predisposition to an early onset of colorectal cancer. The majority of the HNPCC families carry germline mutations of either hMSH2 or hMLH1 genes, whereas germline mutations of hPMS1 and hPMS2 genes have rarely been observed. Almost all of the germline mutations reported so far concern typical HNPCC families. However, there are families that display aggregations of colon cancer even though they do not fulfil all HNPCC criteria (incomplete HNPCC families) as well as sporadic cases of early onset colon cancers that could be related to germline mutations of these genes. Therefore, we screened germline mutations of hMSH2 and hMLH1 genes in 3 groups of patients from France and Turkey: typical HNPCC (n = 3), incomplete HNPCC (n = 9) and young patients without apparent familial history (n = 7). By in vitro synthesis of protein assay, heteroduplex analysis and direct genomic sequencing, we identified 1 family with hMSH2 mutation and 5 families with hMLH1 mutations. Two of the 3 HNPCC families (66%) displayed hMLH1 germline mutations. Interestingly, 4 of 9 families with incomplete HNPCC (44%) also displayed mutations of hMSH2 or hMLH1 genes. In contrast, no germline mutation of these genes was found in 7 young patients. Our results show that germline mutations of hMSH2 and hMLH1 genes contribute to a significant fraction of familial predisposition to colon cancer cases that do not fulfil all diagnostic criteria of HNPCC. Int. J. Cancer 73:831–836, 1997.

Intensity-dependent constitutional MLH1 promoter methylation leads to early onset of colorectal cancer by affecting both alleles.

Constitutional epimutation is one of the causes for MLH1 gene inactivation associated with hereditary non‐polyposis colon cancer (HNPCC) syndrome. Here we investigate MLH1 promoter hypermethylation in 110 sporadic early‐onset colorectal cancer patients. Variable levels of hypermethylation were detected in 55 patients (50%). Importantly a reduced MLH1 gene expression was found in patients with high‐level methylation, with the association of microsatellite instability (MSI) in their tumor cells. Such high‐level methylation accounts for 7.4% of all patients included in this study. Furthermore, we found that in one case constitutional methylation affected both alleles, indicating a post‐zygotic methylation dysregulation. Our findings suggest that constitutional epimutation is a mechanism underlying early‐onset colorectal cancer, although it is involved in only a small proportion of patients, who require appropriate surveillance. Our findings provide further insight into the role of aberrant constitutional methylation in colon carcinogenesis and raise the question of whether prevalent low‐level methylation constitutes a potential risk factor for cancer development.

Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk.

To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case–control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearsons χ2 test, Cochran–Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30–2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11–1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13–1.98; P=0.007 and OR: 1.49, CI: 1.14–1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10–2.37), 2.09 (CI: 1.43–3.07), 2.87 (CI: 1.76–4.70) and 3.88 (CI: 1.72–8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18–2.46), 2.29 (CI: 1.55–3.38) and 6.21 (CI: 2.67–14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.

Prodromal depression in pancreatic cancer: Retrospective evaluation on ten patients

OBJECTIVEnSince the description by Yaskin in 1931, it has been observed that pancreatic cancer and depression are two clinical entities that share a high affinity. This observation relies on the higher incidence of depressive syndromes associated with pancreatic cancer than in any other type of digestive tumor, and on the possible occurrence of depressive symptoms several months before the diagnosis of cancer. We present here a series of cases whose screening returned positive for depression-related diagnoses in the months prior to revelation of the cancer.nnnMETHODnWe employed a structured psychiatric interview based on DSM-IV criteria (SCID-I). The diagnoses considered were major depressive episode, minor depressive episode, and subsyndromal depression. All subjects were free of psychiatric history.nnnRESULTSnSome 15 patients were initially included: 10 presented compatible criteria for a past depressive episode, 2 presented a major depressive episode, 4 met the diagnosis of minor depression, and 4 evidenced subsyndromal depression over the one-year period prior to cancer diagnosis.nnnSIGNIFICANCE OF RESULTSnThis series of cases is consistent with previous work on the subject that suggested an increased vulnerability to depressive events in the premorbid phase of pancreatic cancer. If the possibility of depressive syndromes constituting the early stages of neoplastic disease is a common idea, it is still impossible to determine the natural history of these two disorders and therefore their causal linkage.

4496 Follow-up and laser nd-yag treatment of adenomas in the rectal stump of familial adenomatous polyposis (fap) patients: long term results.

Aim and Background : The risk of rectal cancer development in the rectal stump of FAP patients with ileorectal anastomosis is well known, but the impact of endoscopic follow-up, and coagulation of residual polyps, on this cancer risk remains unclear. We evaluated retrospectively the results of follow-up with Nd-YAG laser destruction of adenomas in the rectal stump of these patients. Methods:We included all patients with classical FAP and ileo-rectal anastomosis followed at our institution between 1975 and 1999. There were 24 patients (12 females, 12 males, mean age 41 years, range 22- 60), with a median delay of 3 years (range 0-23 years) between colectomy and the beginning of the follow-up. Rectoscopy was performed under general anesthesia, with systematic indigo-carmine dye. After histologic confirmation of their adenomatous nature, the majority of visible polyps were treated using Nd-YAG laser with a power of 25 Watts. Biopsies were obtained at each endoscopy from the largest polyps. The number of rectal polyps was evaluated from endoscopic reports and classified in 3 categories: more than 50, 10-50, less than 10 polyps. Results: The 24 patients had 158 laser sessions with a mean of 6/patient (range 1-17), during a median follow-up of 8 years (range 1-18). Three complications (1 hemorrhage, 2 retroperitoneal perforations) were treated medically. The number of rectal polyps at initial endoscopy were: >50, 12 patients; 10-50, 10 patients; 50 polyps initially, 9 with 10-50 polyps initially), and remained stable in 4 (16.6 %) patients (2 with >50 polyps and a follow-up of 9 and 11 years, 2 with