Nicolas Janin

Cancer risk in heterozygotes for ataxia-telangiectasia

Epidemiological studies have suggested that ataxia‐telangiectasia (AT) heterozygotes have a predisposition to cancer, especially breast cancer in women. Now, haplotyping can identify heterozygotes for AT mutation (ATM) in AT families, allowing the risk of cancer associated with ATM heterozygosity status to be better assessed. We report a family study of AT patients, in which we estimated the risk of cancer according to ATM heterozygosity status. We analyzed demographic characteristics and occurrence of cancer in 1,423 relatives of AT patients. Haplotyping was performed in living relatives. The probability of being heterozygotes for ATM was calculated for deceased relatives. The risk of developing cancer was estimated in the cohort of relatives, and expected numbers of cancer cases were calculated from French age period‐specific incidence rates. The number of cancers at all sites in the total population of relatives was not higher than expected. However, significant heterogeneity was found according to ATM heterozygosity status. This is mainly due to the increased risk of breast cancer previously observed in obligate heterozygotes. In obligate heterozygotes, relative risk (RR) was non‐significantly increased for thyroid cancer, leukemia and liver cancer. Risks of ovarian, lung, pancreatic, kidney, stomach and colorectal cancers were non‐significantly increased in the group with 0.5 probability of being heterozygotes. The RR was not significantly increased for any site of cancer, except for breast. Therefore, there is no evidence that specific screening of relatives of AT patients would be justified at particular sites other than the breast. However, the amplitude of the risk of breast cancer estimated in heterozygous women does not appear to justify a separate screening program from that already available to women with a first‐degree relative affected by breast cancer.

Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families

SummaryEpidemiological studies in ataxia telangiectasia (AT) families have suggested that AT heterozygotes could have an increased cancer risk, especially breast cancer (BC) in women. It has also been suggested that an increased sensibility of AT heterozygotes to the effect of ionizing radiation could be responsible for the increased BC risk. BC relative risk (RR) estimation in AT heterozygotes within families ascertained through AT children is presented here. Family data collected included demographic characteristics, occurrence of cancers, past radiation exposures and blood samples. DNA samples were studied using seven ATM linked microsatellites markers allowing AT haplotypes reconstitution. The relative risk of BC was assessed using French estimated incidence rates. A significant increase risk of BC is found among obligate ATM heterozygotes with a point estimate of 3.32 (P = 0.002). BC relative risk calculated according to age is significantly increased among the obligate ATM heterozygotes female relatives with an age ≤ 44 years (RR = 4.55, P = 0.005). The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age ≥ 45 years (RR = 2.48, P = 0.08). The estimated BC relative risk among ATM heterozygotes is consistent with previously published data. However, the increased risk is only a little higher than classical reproductive risk factors and similar to the risk associated with a first-degree relative affected by BC.

Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families

Epidemiological studies have indicated that ataxia‐telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case–control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ‐line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence‐assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype–phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, β‐adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.

BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma

PurposeFrom epidemiological studies it appears that breast cancer (BC) and cutaneous melanoma (CMM) in the same individual occur at a higher frequency than expected by chance. Genetic factors common to both cancers can be suspected. Our goal was to estimate the involvement of “high risk” genes in patients presenting these two neoplasia, selected irrespectively from family history and age at diagnosis.Experimental designEighty two patients with BC and CMM were screened for BRCA1, BRCA2, TP53, CDKN2A and CDK4 (exon 2) germline mutations.ResultsDeleterious mutations were identified in 6 patients: two carriers of a BRCA1 germline mutation, two carriers of TP53 germline mutations (one of which also harbored a BRCA2 deleterious mutation, the other one a BRCA2 unclassified variant), and two carriers of a CDKN2A germline mutation. In addition, 6 variants of unknown signification were identified in BRCA1 or BRCA2 genes. Regarding family history, 3/13 (23%) patients with a positive family history of BC or CMM were carriers of a germline mutation, whereas only 3/69 (4%) patients without family history were carriers of a germline mutation.ConclusionOur findings show that few patients with BC and CMM who lacked family histories of these cancers are carriers of deleterious germline mutations in four of the five genes we examined. We describe for the first time, two simultaneous BRCA2 and TP53 mutations, suggesting that analysis in more than one gene could be performed if a patient’s personal or familial history does not match a single syndrome.

A Simple Model for Carcinogenesis of Colorectal Cancers with Microsatellite Instability

Lynch syndrome is a hereditary predisposition to colorectal cancer (CRC) and other cancers caused by germline mutations in mismatch repair (MMR) genes. Almost all the cancers diagnosed in Lynch syndrome have an acquired MMR deficiency, a replication error (RER) mutator phenotype that is also found in a minority of sporadic cancers developed in the target organs of Lynch syndrome. Lynch syndrome displays many curious features that cannot be accounted for by the prevailing concepts of carcinogenesis and genetics: (1) CRCs occur preferentially in the right side of the colon, whereas the majority of sporadic cases develop in the left colon; (2) the increased risk of CRC is not associated with an increased incidence of adenomatous polyps, which are necessary precancerous lesions in the development of common CRCs; (3) the tumor spectrum in Lynch syndrome is restricted to the colon and some extracolonic sites, whereas the responsible MMR genes are ubiquitously expressed; (4) the tumor risk, which is negligible during childhood, becomes significant during adulthood at the age of 25 and thereafter remains essentially constant throughout the ages. (5) Finally, the sporadic counterparts to the CRCs diagnosed in the setting of Lynch syndrome very curiously develop almost exclusively in the right colon, whereas this right-sidedness is much less pronounced in Lynch syndrome. To explain these anomalies, we propose a model of RER+ carcinogenesis based on the simple idea that the RER mutator phenotype has only short-term viability in normal cells. The proposed model states that the RER+ carcinogenesis is divided into two clearly distinct evolutive phases: (1) a preliminary phase starting with the counter-selective loss of mismatch repair function, in which most clones with the RER mutator phenotype are eliminated through apoptosis or an accelerated aging process; (2) an explosive phase that is initiated only if mutations blocking apoptosis and senescence, rapidly acquired during the short life span of the nontransformed RER+ clones, eventually rescue one RER+ cell that gives rise to the malignant clone. It will be shown that this theoretical framework with its heterodox initiation process not only possesses the virtue of allowing an understanding of Lynch syndrome, but may also have broader applications to all research fields dealing with carcinogenesis.

Ataxia-telangiectasia genes and breast cancer risk in a French family study

Ataxia-telangiectasia (AT) is a rare autosomal recessive early childhood disorder, characterized by progressive neuronal degeneration, immunological deficiency, radiosensitivity and an increased risk of cancer caused in most cases by mutations in the AT-mutated gene (ATM). Epidemiological studies on AT families have shown that AT heterozygous women have an increased risk of developing breast cancer (BC). The ATM protein plays a central role in the recognition and repair of DNA double-strand breaks and the subsequent activation of cell-cycle checkpoints. Whilst AT is a rare disease, 0.5-1 % of the general population are estimated to be AT mutation carriers, thus any increases in the risks of cancer associated with ATM carrier status are of public health relevance. The main results of our published studies on the risk of BC in 34 French AT families according to heterozygote status, type of ATM mutation and exogenous factors are summarized here. The risk of BC was higher in ATM heterozygous (HetATM) women and did not differ significantly according to the type of ATM mutation (missense vs truncating) carried by the AT family members but appeared associated with the position of some truncating mutations in certain binding domains of the ATM protein. The effect of exogenous factors, such as reproductive life factors and exposure to ionizing radiation, on the risk of BC according to ATM heterozygote status was assessed. There was no evidence for interaction (except for age at first full-term pregnancy). These findings does not appear to justify a separate screening program from that already available to other women with a first-degree relative affected by BC, as their risks have similar amplitude. Chest X-rays did not appear to be a risk factor for BC in our study population. More powerful studies, using data sets pooled from international sources are being set up to confirm these observations.

Variation in breast cancer risk of heterozygotes for ataxia-telangiectasia according to environmental factors

Ataxia‐telangiectasia (AT) is a rare autosomal recessive disorder, characterized by progressive neuronal degeneration, immunological deficiency, radio‐sensitivity and an increased risk of cancer. Although several studies have confirmed that AT heterozygosis increases the risk of breast cancer (BC), we do not know how exogenous factors affect this risk. We performed an epidemiological study on the cancer risks associated with AT heterozygosis in France and explored the variation in BC risk according to environmental factors, such as reproductive factors and exposure to ionizing radiation. Information on the amount of ionizing radiation received by an individual in their lifetime and on their reproductive life was collected from the living relatives of 34 AT children (175 female relatives). Consistent with previous reports and with our previous estimate on the entire retrospective cohort, we found that the risk of developing BC is 3.6‐fold higher among ATM heterozygous women. An increased risk was associated with an early age at menarche, a late age at first childbirth, nulliparity, premenopausal status and increasing periods of breast cell mitotic activity (BCMA) prior to the first childbirth. Age at menarche, age at 1st childbirth and BCMA seemed to have a stronger effect in ATM heterozygotes than in non‐ATM heterozygotes. However, the tests were not all statistically significant (only age at 1st childbirth). Surprisingly, the risk of BC decreased when the chest or breasts were irradiated. It is difficult to interpret the data because of the small sample size, but further investigations should provide a biological explanation for the variation in BC risk associated with exogenous factors according to ATM heterozygosis status.

Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?

Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?

Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families.

Both telomere length (TL) and ATM mutations have been associated with cancer susceptibility and ATM participates in the signaling of telomere erosion. We wondered whether carriage of an ATM mutation influences age-related TL shortening and cancer risk in ataxia-telangiectasia families.

PCR-assisted localization of the human SRPR gene

SummaryA polymerase chain reaction (PCR)-based assay has been designed that detects the presence of the human signal recognition particle receptor (SRPR) gene in inter-species somatic cell hybrids. By using hybrids containing various fragments of chromosome 11q, SRPR has been mapped to a chromosomal region flanked by the 11q23 and 11q24 breakpoints associated with the constitutional and neuroepithelioma (11;22) translocations, respectively.