Model for risk adjustment of postoperative mortality in patients with colorectal cancer.

BACKGROUND: A model was developed for risk adjustment of postoperative mortality in patients with colorectal cancer in order to make fair comparisons between healthcare providers. Previous models were derived in relatively small studies with the use of suboptimal modelling techniques. METHODS: Data from adults included in a national study of major surgery for colorectal cancer were used to develop and validate a logistic regression model for 90-day mortality. The main risk factors were identified from a review of the literature. The association with age was modelled as a curved continuous relationship. Bootstrap resampling was used to select interactions between risk factors. RESULTS: A model based on data from 62 314 adults was developed that was well calibrated (absolute differences between observed and predicted mortality always smaller than 0·75 per cent in deciles of predicted risk). It discriminated well between low- and high-risk patients (C-index 0·800, 95 per cent c.i. 0·793 to 0·807). An interaction between age and metastatic disease was included as metastatic disease was found to increase postoperative risk in young patients aged 50 years (odds ratio 3·53, 95 per cent c.i. 2·66 to 4·67) far more than in elderly patients aged 80 years (odds ratio 1·48, 1·32 to 1·66). CONCLUSION: Use of this model, estimated in the largest number of patients with colorectal cancer to date, is recommended when comparing postoperative mortality of major colorectal cancer surgery between hospitals, clinical teams or individual surgeons.

The rising incidence of anal cancer in England 1990-2010: a population-based study.

AIM: Although anal cancer is rare, its incidence has been reported to be rising in several countries. This study aimed to determine whether there have been any changes in incidence over time in England. METHOD: In the cancer registry component of the English National Cancer Data Repository, 13 940 patients were identified with a primary diagnosis of anal cancer made between 1990 and 2010. Tumours were grouped according to the ICD-O morphology codes into squamous cell carcinoma, basaloid and cloacogenic carcinoma, adenocarcinoma and other cancer types. The incidence over this period was investigated in relation to type of tumour, age and sex. RESULTS: In men there was a 69% increase in squamous cell anal carcinoma from 0.43 per 100 000 population in 1990-94 to 0.73 in 2006-10. For women these rates were 0.50 in 1990-94 and 1.13 in 2006-10, a rise of 126%. CONCLUSION: The study showed that between 1990 and 2010 there was a substantial rise in the incidence of anal cancer in England. This effect was more marked in women than men.

Early mortality from colorectal cancer in England: a retrospective observational study of the factors associated with death in the first year after diagnosis.

BACKGROUND: The United Kingdom performs poorly in international comparisons of colorectal cancer survival with much of the deficit owing to high numbers of deaths close to the time of diagnosis. This retrospective cohort study investigates the patient, tumour and treatment characteristics of those who die in the first year after diagnosis of their disease. METHODS: Patients diagnosed with colon (n=65,733) or rectal (n=26,123) cancer in England between 2006 and 2008 were identified in the National Cancer Data Repository. Multivariable logistic regression was used to investigate the odds of death within 1 month, 1-3 months and 3-12 months after diagnosis. RESULTS: In all, 11.5% of colon and 5.4% of rectal cancer patients died within a month of diagnosis: this proportion decreased significantly over the study period. For both cancer sites, older age, stage at diagnosis, deprivation and emergency presentation were associated with early death. Individuals who died shortly after diagnosis were also more likely to have missing data about important prognostic factors such as disease stage and treatment. CONCLUSION: Using routinely collected data, at no inconvenience to patients, we have identified some important areas relating to early deaths from colorectal cancer, which merit further research.

Population-based study of laparoscopic colorectal cancer surgery 2006-2008.

BACKGROUND: Clinical guidelines recommend that, where clinically appropriate, laparoscopic tumour resections should be available for patients with colorectal cancer. This study aimed to examine the introduction of laparoscopic surgery in the English National Health Service. METHODS: Data were extracted from the National Cancer Data Repository on all patients who underwent major resection for a primary colorectal cancer diagnosed between 2006 and 2008. Laparoscopic procedures were identified from codes in the Hospital Episode Statistics and National Bowel Cancer Audit Project data in the resource. Trends in the use of laparoscopic surgery and its influence on outcomes were examined. RESULTS: Of 58 135 resections undertaken over the study period, 10 955 (18·8 per cent) were attempted laparoscopically. This increased from 10·0 (95 per cent confidence interval (c.i.) 8·1 to 12·0) per cent in 2006 to 28·4 (25·4 to 31·4) per cent in 2008. Laparoscopic surgery was used less in patients with advanced disease (modified Dukes' stage 'D' versus A: odds ratio (OR) 0·45, 95 per cent c.i. 0·40 to 0·50), rectal tumours (OR 0·71, 0·67 to 0·75), those with more co-morbidity (Charlson score 3 or more versus 0: OR 0·69, 0·58 to 0·82) or presenting as an emergency (OR 0·15, 0·13 to 0·17). A total of 1652 laparoscopic procedures (15·1 per cent) were converted to open surgery. Conversion was more likely in advanced disease (modified Dukes' stage 'D' versus A: OR 1·56, 1·20 to 2·03), rectal tumours (OR 1·29, 1·14 to 1·46) and emergencies (OR 2·06, 1·54 to 2·76). Length of hospital stay (OR 0·65, 0·64 to 0·66), 30-day postoperative mortality (OR 0·55, 0·48 to 0·64) and risk of death within 1 year (hazard ratio 0·60, 0·55 to 0·65) were reduced in the laparoscopic group. CONCLUSION: Laparoscopic surgery was used more frequently in low-risk patients.

Nonresectional management of colorectal cancer: multidisciplinary factors that influence treatment strategy.

AIM: Surgical resection of a primary colorectal tumour remains the treatment of choice and offers the best chance of cure. However, in some patients, resection is not achieved. There are few published data on this group of patients. The aim of this study was to evaluate this group to determine the frequency and reasons for nonresection, and to analyse the subsequent management. METHOD: A retrospective review was performed using a Trust colorectal cancer database and individual electronic patient records. Patients who presented to our unit with a diagnosis of primary colorectal cancer managed by nonresectional intervention over a 2-year period were identified. Data analysed included: patient demographics, radiological staging, histological data, nonsurgical therapy, tumour-specific complications and requirement for palliative surgical procedures. RESULTS: A total of 671 patients were identified with primary colorectal cancer. One hundred and fifty-six (23%) were managed without resection, following discussion at a multidisciplinary team meeting. Of 156 patients, histological confirmation was obtained in 131 (84%), with the remainder of the diagnoses being based on unequivocal radiological imaging and/or operative findings. Complete radiological staging was achieved in 150 (96%) patients. The predominant reasons for nonresectional management were: advanced metastatic disease (66%), significant medical comorbidity (19%) and patient refusal (6%). Fifty-nine of 156 patients (38%) subsequently received palliative chemotherapy, 9 (6%) radiotherapy and or 9 (6%) combination chemo-radiotherapy. Seventy-nine (51%) of 156 patients received no therapy other than best supportive palliative care, for reasons including significant medical comorbidity (62%) and patient refusal (19%). Following the initial decision not to resect, 68 (44%) patients did at some point undergo some form of palliative intervention (stenting, stoma or bypass) for obstruction - 44 (28%) electively and 24 (15%) as an emergency. CONCLUSION: Nonresectional management of patients with primary colorectal cancer is not an uncommon outcome following discussion at a multidisciplinary meeting. In these patients, nonsurgical palliation should be employed when necessary, though is frequently limited by comorbidity. However, subsequent surgical palliation is still required in a substantial proportion of cases.

A retrospective observational study examining the characteristics and outcomes of tumours diagnosed within and without of the English NHS Bowel Cancer Screening Programme.

BACKGROUND: Colorectal cancer is common in England and, with long-term survival relatively poor, improving outcomes is a priority. A major initiative to reduce mortality from the disease has been the introduction of the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP). Combining data from the BCSP with that in the National Cancer Data Repository (NCDR) allows all tumours diagnosed in England to be categorised according to their involvement with the BCSP. This study sought to quantify the characteristics of the tumours diagnosed within and outside the BCSP and investigate its impact on outcomes. METHODS: Linkage of the NCDR and BCSP data allowed all tumours diagnosed between July 2006 and December 2008 to be categorised into four groups; screen-detected tumours, screening-interval tumours, tumours diagnosed in non-participating invitees and tumours diagnosed in those never invited to participate. The characteristics, management and outcome of tumours in each category were compared. RESULTS: In all, 76 943 individuals were diagnosed with their first primary colorectal cancer during the study period. Of these 2213 (2.9%) were screen-detected, 623 (0.8%) were screening-interval cancers, 1760 (2.3%) were diagnosed in individuals in non-participating invitees and 72 437 (94.1%) were diagnosed in individuals not invited to participate in the programme due to its ongoing roll-out over the time period studied. Screen-detected tumours were identified at earlier Dukes' stages, were more likely to be managed with curative intent and had significantly better outcomes than tumours in other categories. CONCLUSION: Screen-detected cancers had a significantly better prognosis than other tumours and this would suggest that the BCSP should reduce mortality from colorectal cancer in England.

Low abdominoperineal excision rates are associated with high-workload surgeons and lower tumour height. Is further specialization needed?

AIM: Wide variation, independent of disease extent and case mix, has been observed in the rate of use of abdominoperineal excision (APE) for rectal cancer. Previous analyses have, however, been confounded by failure to adjust for the location of the tumour within the rectum. This population-based study sought to examine whether variations in tumour height explained differences in APE use. METHOD: Information was obtained on all individuals who underwent a major resection for a rectal tumour diagnosed between 1998 and 2005 across the Northern and Yorkshire regions of the UK. Median distances from the dentate line were calculated for all tumours excised by APE and compared with rates of use of APE between specialists and nonspecialist surgeons and across hospital trusts. RESULTS: The completeness of pathological reporting of height of tumour within the rectum was variable. A low rate of APE use was associated with a lower median distance of tumours from the dentate line. Specialist colorectal cancer surgeons performed fewer APEs on patients with a tumour located lower in the rectum than nonspecialist surgeons. CONCLUSION: Variations in the height of tumour did not explain the variation in APE use. Specialist high-volume surgeons undertook fewer APEs and those they performed were closer to the dentate line than low-volume nonspecialist surgeons.

Measurement of anal cushions in continent women.

AIM: Anal cushions are connective tissue complexes thought to be involved in anal continence. This study aimed to assess them in continent subjects. METHOD: Continent women undergoing a transvaginal ultrasound scan for gynaecological reasons were included. The anal cushions were visualized at the mid-canal level. The cross-sectional area within the internal anal sphincter (Area 1) and the area enclosed within the anal cushions (Area 2) were measured and a Cushion:Canal (C:C) ratio was derived for each patient. The measurements were repeated in the semi-erect position. RESULTS: One hundred and two patients with a median age of 41 (IQR 32-49) years were included. The median C:C ratio was 0.68 (IQR 0.61-0.73). Inter-observer error was 0.98 and intra-observer error was 0.99. There was no significant correlation between age and C:C ratio. The C:C ratio was significantly higher in parous than in nulliparous women (P = 0.04). A history of obstetric trauma or minimal haemorrhoidal symptoms did not influence C:C ratio. There was a significant increase in C:C ratio in the erect position. (P = 0.04). CONCLUSION: There was a wide range of variability in the measurement of anal cushions in normal continent women. These were not influenced by age.

Prognostic factors for survival after curative resection of Dukes' B colonic cancer.

AIM: Data on the prognostic factors for survival in patients with locally advanced, node-negative colon cancer are limited. This study aimed to determine which factors might predict survival in patients with Dukes' B (T3 or T4, N0) colon cancer. METHOD: One hundred and eighty (93 male; median age 75 [range, 38-96] years) consecutive patients who had resection of a primary Dukes' B (on final histopathological analysis) colonic cancer between 1998 and 2003 were studied. No patient received neoadjuvant chemotherapy. Multivariate Cox regression modelling was used to assess the prognostic value of variables. Median follow up was 85 (60-125) months. RESULTS: Thirteen (7%) patients had a perforation at presentation. The median distance from tumour to the nearest longitudinal resection margin was 6 (0.3-27) cm. One hundred and twenty-four (69%) patients had a lymph node yield of 12 or more nodes. Actual 5-year survival was 59%. On multivariate regression analysis, tumour perforation (perforation vs no perforation, 5-year survival, 23%vs 61%; hazard ratio (HR), 3.7; 95% confidence interval (CI), 1.6-8.4; P = 0.002), tumour-to-margin distance (< 5 cm vs ≥ 5 cm, 48%vs 65%; HR, 1.7; 95% CI, 1.1-2.7; P = 0.039) and older age (≥ 75 years vs < 75 years, 45%vs 72%; HR, 3; 95% CI, 1.8-5; P < 0.001) were independent significant variables. CONCLUSION: A lymph node yield of 12 or more nodes is not a significant prognostic factor for survival after resection of Dukes' B colonic cancer. Patients with tumour perforation or limited resection have worse prognosis.

Time to Surgery Following Short-Course Radiotherapy in Rectal Cancer and its Impact on Postoperative Outcomes. A Population-Based Study Across the English National Health Service, 2009-2014.

AIMS: Preoperative short-course radiotherapy (SCRT) is an important treatment option for rectal cancer. The length of time between completing SCRT and surgery may influence postoperative outcomes, but the evidence available to determine the optimal interval is limited and often conflicting. MATERIALS AND METHODS: Information was extracted from a colorectal cancer data repository (CORECT-R) on all surgically treated rectal cancer patients who received SCRT in the English National Health Service between April 2009 and December 2014. The time from radiotherapy to surgery was described across the population. Thirty-day postoperative mortality, returns to theatre, length of stay and 1-year survival were investigated in relation to the interval between radiotherapy and surgery. RESULTS: Within the cohort of 3469 patients, the time to surgery was 0-7 days for 76% of patients, 8-14 days for 19% of patients and 15-27 days for 5% of patients. There was a clear variation in relation to different patient characteristics. There was, however, no evidence of differences in postoperative outcomes in relation to interval length. CONCLUSIONS: This study suggests that the time interval between SCRT and surgery does not influence postoperative outcomes up to a year after surgery. The study provides population-level, real-world evidence to complement that from clinical trials.

Measurement of anal cushions in idiopathic faecal incontinence.

BACKGROUND: Faecal incontinence affects a heterogeneous population and aetiology can be multifactorial. In a subset of patients the aetiology remains idiopathic despite standard investigations. Anal cushions are important in normal continence, but have rarely been studied. The aim of this study was to measure the size of the anal cushions and to evaluate their role in patients with idiopathic faecal incontinence. METHODS: Women in whom idiopathic faecal incontinence was diagnosed after standard anorectal investigations underwent transvaginal ultrasonography. The area of the anal cushions was measured and a cushion : canal (C : C) ratio derived, which was compared with that in a control group of women without faecal incontinence. RESULTS: Some 21 patients with incontinence (median age 60 years) and 102 asymptomatic controls (median age 41 years) underwent scanning. The median (interquartile range) C : C ratio in the symptomatic group was significantly lower than that for controls (0.57 (0.54-0.66) versus 0.68 (0.61-0.73) respectively; P = 0.001). C : C ratio was not influenced by age (r = 0.023, P = 0.821). CONCLUSION: The C : C ratio was reduced in patients with idiopathic faecal incontinence.

Efficacy of the anal fistula plug in complex anorectal fistulae.

OBJECTIVE: The treatment of complex anorectal and rectovaginal fistulae remains a difficult problem. The options are fistulotomy, setons, fibrin glue and a variety of flap procedures. Recently, there have been several reports of a new plug; the Surgisis AFP plug. Reports from various centres do not give consistent results. The aim of this study was to assess the efficacy of the Surgisis AFP fistula plug in a wide spectrum of patients with anorectal, rectovaginal and pouch vaginal fistulae. METHOD: Between March 2006 and September 2007, patients with a variety of anal fistulae were selected for fistula plug insertion in the coloproctology units at Leeds, UK, and Aarhus, Denmark. Demographic and fistulae details were obtained. Postoperatively, all patients had a course of oral antibiotics. RESULTS: Forty-three patients with a median age of 45 (range 18-65) years underwent a total of 45 procedures. Seventy-five per cent (n = 32) had a fistula secondary to cryptoglandular abscess. Median follow up was 47 (range 12-77) weeks. The success rate for complete healing was 44%. Dislodgement caused failure on 10 (22%) occasions. CONCLUSION: Our study shows a moderate success rate for treatment with fistula plugs. The complex nature of the fistulae selected may be the reason for the low success rate.

Morbidity and mortality after closure of loop ileostomy.

BACKGROUND: A temporary loop ileostomy is commonly used to protect low pelvic anastomoses. Closure is associated with morbidity and mortality. This study investigated patterns of complications after loop ileostomy closure and factors associated with morbidity and mortality. METHOD: A review was performed of patients who underwent loop ileostomy closure between 1999 and 2005. RESULTS: Three hundred and twenty-five patients underwent closure of loop ileostomy. Reasons for primary surgery were: anterior resection for cancer (n = 160, 49%), ileal pouch-anal anastomosis (n = 114, 35%), diverticular disease (n = 25, 8%), Crohn's colitis (n = 4, 1%) and other conditions (n = 22, 7%). Overall mortality was 2.5% (n = 8) and morbidity was 22.8% (n = 74). Thirty-two patients (10%) developed small bowel obstruction, of whom seven required operative intervention. Overall, the re-operation rate in this series was 28 patients (8.6%). Thirteen (4%) patients had an anastomotic leak of whom 12 patients had re-operation. Preoperative anaemia was significantly associated with leakage (Hb < 11 g/dl; n = 65, P = 0.033). The leakage rate was lower after a stapled anastomosis than a hand-sutured anastomosis (4/203 vs 9/122; P = 0.039). Hypo-albuminaemia (albumin < 34 g/l) was significantly associated with mortality (n = 46, P < 0.001). CONCLUSIONS: Loop ileostomy closure is associated with morbidity and mortality. Anaemia and hypo-albuminaemia may be associated with poor outcome.

A classification system for faecal incontinence based on anorectal investigations.

BACKGROUND: Faecal incontinence is a socially disabling condition that affects a heterogeneous population of patients. There is no standardization of investigations, and treatment outcomes are variable. The major limitation for comparing the results from different studies is the lack of a pretreatment classification of incontinence. The aim of this study was to review the anorectal investigation findings and propose a simple, repeatable classification for faecal incontinence. METHODS: Patients who had anorectal investigations for defaecatory disorders from February 2000 to September 2006 were analysed retrospectively. All patients had anorectal manometry, anal mucosal electrosensitivity testing and endoanal ultrasonography. RESULTS: Of a total of 1294 patients, 135 were excluded, leaving 1159 (460 continent and 699 incontinent) for analysis. The patients were divided into four groups: traumatic incontinence, neuropathic faecal incontinence, combined faecal incontinence and idiopathic faecal incontinence. The manometric variables and demographics were distinct in these groups. CONCLUSION: Patients with faecal incontinence can be classified into different groups with distinct pathophysiological variables. Such a classification system will enable comparison and interpretation of the outcomes of different studies and also help in the selection of patients for appropriate treatments.

Awareness of investigations and treatment of faecal incontinence among the general practitioners: a postal questionnaire survey.

OBJECTIVE: Faecal incontinence is a distressing condition that can result in significant embarrassment and limitation of routine activities. General practitioners (GP) are the primary carers of such patients. There are recent developments in the surgical treatment options for this under-reported condition. Awareness of these changes is required to make the best use of them. To the best knowledge of the authors, no studies have examined the awareness of investigations and treatment options for faecal incontinence amongst GPs. This is the focus of our study. METHOD: A confidential questionnaire was posted to GPs in the Yorkshire region. The questionnaire was designed to assess: first, the basic knowledge of GPs with regard to prevalence, investigations and treatment modalities of faecal incontinence and secondly, the patterns of consultations and referrals of patients with faecal incontinence. RESULTS: One thousand and one hundred questionnaires were posted. Five hundred and four were returned giving a response rate of 48.5% (n = 504). The prevalence assessed by the GPs is similar to that by population based surveys. Only 32% (n = 162) of GPs were aware of at least one investigation. Similarly only 32% of the GP's were aware of at least one form of surgical treatment. The knowledge of UK centres where these facilities are available was limited (60% not aware). Only one quarter of the GPs referred the patients to the surgical specialties. Surprisingly, there was no significant difference in the level of knowledge of investigation and treatments between the GPs who see patients with faecal incontinence more frequently compared with those who see such patients infrequently (P-values 0.298 and 0.432 respectively). CONCLUSION: The level of awareness of investigation modalities and treatment options for faecal incontinence is limited among GPs. Knowledge of the existence of diagnostic tests and surgical treatment options for faecal incontinence and the centres with these facilities is needed for the best utilization of the technical resources and expertise. Further studies are needed to assess the impact of this lack of knowledge on the quality of patient care. Better communication between referral centres and GPs, combined with continuing medical education programmes, may be useful tools to improve appropriate patient management.

The outcome of loop ileostomy closure: a prospective study.

BACKGROUND: The use of a loop ileostomy is an effective method to protect pelvic anastomoses, although there is some debate as to the routine use of a stoma. A second operation is required to close the stoma, with potential complications. OBJECTIVE: The aim of this study was to assess prospectively the morbidity of closure of loop ileostomy. METHOD: All patients scheduled for loop ileostomy closure over a 12-month period were included. The patient demographics, operative technique, complications and length of stay were recorded prospectively. RESULTS: Fifty consecutive patients (28 males and 22 females) with a median age (interquartile range, IQR) of 56 (42-73) years underwent closure of loop ileostomy, at a median time (IQR) of 29 (18-48) weeks after formation. Twelve patients (24%) developed complications: six (12%) had intestinal obstruction of which one required a laparotomy, four (8%) had wound infections of which one required re-operation, one (2%) had an ileal anastomotic leak and subsequently died and one (2%) died from a myocardial infarction. The median length (IQR) of hospital stay was 8 (7-10) days. CONCLUSION: We have demonstrated that a quarter of patients develop complications after loop ileostomy closure. The majority of these are minor. Methods to reduce the number of complications, such as optimum time for closure and distal limb irrigation techniques, need to be studied.

Awareness of risk factors amongst first degree relative patients with colorectal cancer.

BACKGROUND: The association between family history of colorectal cancer (CRC) in first degree relatives (FDRs) and the risk of developing the disease has been well established. However, little is known about the degree of awareness of CRC risk factors amongst FDRs. This study examined awareness of familial, dietary and lifestyle risk amongst FDRs. METHOD: Consent to approach relatives was obtained from CRC patients who attended outpatients following surgery for CRC. A study specific questionnaire was sent by post to their FDRs. The dietary and lifestyle risk factors tested in the questionnaire were those promoted in CRC educational material. RESULTS: One hundred and four questionnaires were returned out of 137 sent (76%). Fifty-nine per cent (n = 61) of FDRs were aware of their increased risk. Fifty-five per cent (n = 57) were aware of the link between CRC and smoking; however, knowledge of association of CRC with excessive alcohol consumption (32%) and lack of exercise (40%) was less well appreciated. Higher awareness scores were obtained by those with a university education (P < 0.001). Ninety four per cent believed that relatives of CRC patients were not provided with enough information as to their being at risk and risk factors. CONCLUSIONS: This study provides an initial assessment of the awareness of CRC risk factors in a population at increased risk. It demonstrates a poor level of knowledge. Improved education strategies allowing FDRs to make dietary and lifestyle modifications that could reduce their lifetime risk of developing CRC are necessary.

Human blood group isoantigen expression on normal and malignant gastric epithelium studied with anti-A and anti-B monoclonal antibodies.

Variation in human blood group isoantigen expression on normal and malignant gastric epithelium was demonstrated with monoclonal antibodies to blood groups A and B in an indirect immunoperoxidase technique. The expected isoantigen expression was demonstrated on endoscopic biopsy specimens of normal gastric mucosa from 11 patients. Of 17 patients with gastric carcinoma (blood group A, 15; blood group AB, 2), complete loss of isoantigen expression was noted in 6 (35%). In these 6 patients, blood group isoantigen remained both in the adjacent uninvolved mucosa and at the margin of resection. The loss of isoantigen did not appear to be related to the degree of differentiation within the tumor, to the secretor status of the patient, or to the blood subgroup. Lymph node metastases reflected the isoantigen status of the primary tumor, being positive in 5 of 6 expression in all 17 patients or in an additional 15 patients studied with blood group O. These findings were discussed in the light of previously reported work on the localization of blood group isoantigens on malignant and nonmalignant gastric epithelium with the use of conventional antisera and a variety of immunohistologic techniques.

Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlh1 mutations.

Hereditary nonpolyposis colorectal carcinoma is a major cancer susceptibility syndrome known to be caused by inheritance of mutations in at least four genes such as hMSH2, hMLH1, hPMS1, and hPMS2 which encode components of a DNA mismatch repair system. The hMLH1 genomic locus on chromosome 3p has been cloned and shown to cover approximately 58 kilobases of genomic DNA and contain 19 exons. The sequence of all of the intron-exon junctions has been determined and used to develop methods for analyzing each hMLH1 exon for mutations. Using these methods to analyze a 3p-linked hereditary nonpolyposis colorectal carcinoma kindred, we have demonstrated that cancer susceptibility in this family is due to the inheritance of a frame shift mutation in the hMLH1 gene.